Effect of Eudragit on the Mechanical and Mucoadhesion Properties of Polycarbophil Dosage Forms

8/12/2019 Effect of Eudragit on the Mechanical and Mucoadhesion Properties of Polycarbophil Dosage Forms

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ELSEVIER Journal of Controlled Release 45 (1997) 57-64

journ l ofc o n t r o l l e dr e l e s e

Th e e f f e c t o f Eu d r a g it R L 1 0 0 o n th e m e c h a n i c a l a n dm u c o a d h e s i o n p r o p e rt ie s o f p o l y c a r b o p h i l d o sa g e f o rm s 1

Boaz T i rosh , Muhammad Ba luom, Tahe r Nassa r , Michae l Fr i edman, Abraham Rubins t e inThe Heb rew Universi ty of Jerusalem Scho ol of Pharmacy P.O. Box 12065 Jerusalem 91120 Israel

Received 26 April 1996; revised 27 August 1996; accepted 30 August 1996

A b s t r a c t

Polycarbophi l is a high molecular weight acrylic polymer which posses enzymatic inhibition and absorption enhancementproperties, However, its use is limited because of poor mechanical properties. In this study Eudragit RL-100 was tested asa possible regulat ing agent for polycarbophil solid formulations. Although swelling of polycarbophi l-Eudragit RL-100films was lower in PBS pH=5.0 than in PBS pH=7.4, in both cases there was a profound difference between the swelling ofpure polycarbophil films and films made of mixtures of polycarbophil and increasing amounts of Eudragit RL-100.Eudragit RL-100 was able to significantly decrease the swelling of polycarbophil films in a concentration-dependentmanner. The incorporation of Eudragit@ RL-100 into polycarbophil also affected the mechanical properties of the films, aswas evident from the torsion force and modulus of elasticity measurements. The higher the amount of Eudragit RL-100 inthe mixtures with the polycarbophil, the larger the values of torsion force and modulus of elasticity. In the case of tabletsmade of different ratios of Eudragit RL-100 and polycarbophil, the larger the amount of Eudragit RL-100 the higher therate of erosion of the tablet. Tablets containing predetermined ratios of polycarbophil and Eudragit@ RL-100 were able tosynchronize the release rate of sodium cefazolin and ibuprofen. It was found that the similarity in the release rates resultedfrom a controlled erosion process governed by balancing the ratio of Eudragit@ RL-100 and polycarbophil. Themucoadhesion properties of polycarbophil-Eudragit RL-100 tablets with increasing amounts of Eudragit RL-100 wasmeasured in different regions of the GI tract of the rat. It was found that tablets containing up to 20%w/w of Eudragit@RL-100 adhered significantly better to the cecum of the rat and that their adherence to the stomach, jejunum and colon didnot differ from each other. Eudragi t RL-100 concentrations of 50%w/w and above significantly reduced the ability ofpolycarbophil to adhere to the GI epithelium. Based on the reported findings it is suggested that solid dosage forms made ofmixtures of polycarbophi l and Eudragit RL-100 may be suitable for the oral delivery of drugs, such as proteinaceous drugs,susceptible to enzymat ic degradation.K e y w o r d s : Polycarbophil; Eudragit; Sodium cefazolin; Ibuprofen; Synchronized release; Erosion; Mucoadhesion

*Corresponding author.~The results reported here form part of the dissertationprojectsof M.B. and T.N., completed in partial fulfilment of the require-ments of their respective PhD and MSc degrees at the HebrewUniversity of Jerusalem. The study has been presented in part atthe 22nd International Symposium on Controlled Release ofBioactive Materials, Seattle, WA, 1995.

1 I n t r o d u c t i o n

The common approach to increase bioavailabilityof drugs, such as proteinaceous drugs, susceptible togastrointestinal (GI) enzymatic degradation, is to

0168-3659/97/ 17.00 Copyright 1997 Elsevier Science Ireland Ltd. All rights reservedP I I S0168-3659(96)01545-3


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58 B. Tirosh et al. / Journal of Controlled Release 45 1997) 57-64i n c o r p o r a t e e n z y me in h ib i t o r s i n t h e i r d e l i v e r y sy s -t e ms . S in c e mo s t p e p t id e d r u g s a r e a l so l a r g e mo le -c u l e s t h e y r e q u i r e t h e p r e se n c e o f a b so r p t i o n e n -h a n c e r s t o o v e r c o me G I e p i t h e l i a l b a r r i e r s [ 1 ] .N u me r o u s a b so r p t i o n e n h a n c e r s a n d p r o t e a se i n -h ib i t o r s h a v e p r e v io u s ly b e e n su g g e s t e d t o a id t h ea b so r p t i o n o f p r o t e in a c e o u s d r u g s a f t e r o ra l i n g e s t i o n[2,3].

R e c e n t ly , L e h r , L u e s se n e t a l . h a v e r e p o r t e d t h a tmu c o a d h e s iv e p o ly me r s su c h a s a n io n i c p o ly c a r -b o p h i l ( P C P ) a n d C a r b o p o l 9 3 4 p o s s e ss a b s o r p t i o ne n h a n c e me n t p r o p e r t i e s a s a n a ly z e d i n v i t r o w i th t h ep e p t id e p r o b e 9 - d e sg ly c in a mid e , 8 - a r g in in e v a so p -r e s s in ( D G A V P ) [ 4 ]. Mo r e o v e r , p o ly c a r b o p h i l a n dC a r b o p o l 9 3 4 w e r e a b l e t o p r o t e c t D G A V P f r o mmu c o sa l h o mo g e n a t e d e g r a d a t i o n [ 5 ] , a n d i n h ib i tt r y p s in a c t i v i t y , a s a n a ly z e d b y N - ~ - b e n z o y l - l - a r -g in ine e thy les te r deg rada t io n s tud ies [6].

T h e p r o t e o ly s i s i n h ib i t i o n c h a r a c t e r i s t i c s o f P C P ,w h ic h w a s v e r i f i e d b y B a i e t a l. [ 7 ] , w a s f o u n d to b ee f f e c t i v e i n a q u e o u s su sp e n s io n s , w h i l e p o ly ( H E M A )p a r t i c l e s c o a t e d w i th P C P w e r e f o u n d to b e i n e f f e c -t i v e [ 5 ] . I t w a s t h e r e f o r e c o n c lu d e d t h a t a n o p t ima lP C P s o l i d d o s a g e f o r m w o u l d b e o n e w h i c h w o u l dr e l e a se a n d d i sp e r se t h e p o ly me r a s f a s t a s p o s s ib l e[ 8 , 9 ] . H o w e v e r , t h e f a s t r e l e a se a p p r o a c h d o e s n o tt a k e i n to c o n s id e r a t i o n t h e l a r g e d i l u t i o n e f f e c t o fd ispe rsed so l ids in the GI f lu ids [10] .

A n a l t e r n a t i v e a p p r o a c h t o t h e f a s t g e l - f o r min ga n d r a p id d r u g r e l e a se d o sa g e f o r ms w o u ld b e o n ew h ic h w o u ld p r o v id e a c o n s t a n t su p p ly o f t h ep r o t e c t i v e p o ly me r o v e r t ime . S o l id P C P c a r r i e r c a nb e f o r mu la t e d i n to e i t h e r a n e r o d ib l e f i lm o r a ne r o d ib l e t a b le t . B o th f o r m u la t i o n s a r e p r o b l e ma t i c a sP C P f i lms sw e l l r a p id ly w h i l e P C P p o w d e r i s h ig h lyc o mp r e s s ib l e a n d g iv e s v e r y h a r d t a b l e t s . T h e r e f o r e ,t h e a d d i t i o n o f h y d r o p h o b ic p o ly me r i s r e q u i r e d t or e d u c e t h e sw e l l i n g p r o p e r t i e s i n t h e c a se o f P C Pf i lms a n d t o d e c r e a se h a r d n e s s i n t h e c a se o f t a b l e t so f P C R E u d r a g i t R L - 1 0 0 ( E R L ) c o u l d b e u s ed f o rth a t p u r p o se [ 11 ] a n d i n t h is s t u d y w a s e x a m in e d f o ri ts a b i l i t y t o r e g u l a t e t h e m e c h a n ic a l ( a n d h e n c e , t h ee r o s io n ) p r o p e r t i e s o f P C P f i lms a n d t a b l e t s . T h eo u tc o me o f t h e s t u d y c o u ld l e a d t o t h e c o n s t r u c t i o no f a d o sa g e f o r m w h ic h w i l l b e a b l e t o r e l e a se i t sd r u g l o a d t o g e th e r w i th p r e d e t e r min e d a mo u n t s o fP C P r e su l t in g f r o m th e c a r r i e r ' s e r o s io n . I t i s f u r th e ra s su me d th a t i f a n e r o d ib l e d o sa g e f o r m c o u ld b e

a c h i e v e d , a sy n c h r o n i z e d r e l e a se o f a t l e a s t tw op r o b e s p o s se s s in g d i f f e r e n t p h y s i c o - c h e mic a l p r o p -e r t ie s ( e .g . , low and h igh wa te r so lubi l i ty ) i s a t ta in-a b l e . A c o n t r o l l e d , sy n c h r o n i z e d r e l e a se is su g g e s t e das a so lu t ion for in te s t ina l absorp t ion of drugs tha tr e q u i r e c o n s t a n t a b s o r p t i o n p r o m o t i o n o r e n z y m ein h ib i t i o n , s i n c e ' c l o se d c o mp a r tme n t ' c o n d i t i o n s( th a t e x i s t i n sma l l v o lu me b o d y c a v i t i e s su c h a s t h enasa l and rec ta l cav i t ie s ) do not ex is t in the a l imen-t a r y c a n a l [ 1 0 , 1 2 ]. T h e u se o f P C P a s a n e r o d ib l ed r u g p l a t f o r m i s a d v a n t a g e o u s , a l so , b e c a u se o f i t sr e p o r t e d mu c o a d h e s io n p r o p e r t i e s t h a t e n a b l e i n t i -ma te c o n t a c t b e tw e e n t h e d r u g c a r r i e r a n d t h ein te s t ina l ep i the l ium [13] .

T h e o v e r a l l g o a l o f t h e s t u d y w a s t o c h a r a c t e r i z eth e su i t a b i l it y o f P C P - E R L , i n d i f f e r e n t p h y s i c a ls ta te s , to se rve a s an ora l d rug p la t form for drugsth a t r e q u i r e sy n c h r o n i z e d r e l e a se a s a r e su l t o fd i f f e r e n t p h y s i c o c h e mic a l p r o p e r t i e s . Mo r e sp e c i f i -ca l ly , the s tudy was a imed a t : ( a ) measur ing thee f f e c t o f E R L o n t h e m e c h a n i c a l p r o p e r t i e s o f P C Pf i lms , ( b ) me a su r in g t h e e f f e c t o f E R L o n t h eme c h a n ic a l p r o p e r t i e s o f P C P t a b l e t s , a n d ( c )m e a s u r i n g t h e e f f e c t o f E R L o n t h e m u c o a d h e s i o np r o p e r t i e s o f P C P in d i f f e r e n t l o c a t i o n s i n t h e G It rac t o f the ra t .

2 Ex per i menta lA l l ma te r i a l s a n d r e a g e n t s w e r e p u r c h a se d f r o m

S ig ma , S t . L o u i s , MO , u n l e s s o th e r w i se me n t io n e d i nth e t e x t . W a te r w a s d o u b ly d i s ti l le d . P C P w a so b t a i n e d f r o m B . F . G o o d r i c h ( U S A ) a n d E R L w a sp u r c h a s e d f r o m R o h m - P h a r m a ( G e r m a n y ) . A l l s o l -v e n t s w e r e H P L C g r a d e .2.1. PCP- ERL mix ture preparat ion

I n d i f f e r e n t e x p e r ime n t s P C P h y d r o g e l s c o n t a in in g0 , 5 , 1 0, 2 0 , 5 0 mad 7 5 w /w o f E R L w e r e p r e p a r e da s f o l l o w s : E R L w a s d i s so lv e d i n me th a n o l a n d t h eme th a n o l i c so lu t i o n w a s a d d e d t o P C P me th a n o l i cd i sp e r s io n . T h e d i f f e r e n t r a t i o s w e r e a c h i e v e d b ya d d in g m e th a n o l i c so lu t i o n s o f E R L in i n c r e a s in gc o n c e n t r a t i o n s t o a c o n s t a n t a mo u n t ( 1 g ) o f P C Pp r e d i s p e r s e d ( 2 h ) i n 3 5 - 4 0 m l m e t h a n o l u n d e rc o n t in u o u s s t i r r i n g . A f t e r e a c h a d d i t i o n a h o mo g e n -


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B. Tirosh et al . / Journal of Controlled Release 45 1997) 57-64 59o u s , l o w -v i s c o u s g e l w a s fo rm e d a n d s t i r r e d fo r a nadd i t iona l 2 h .

2 .2 . P C P - E R L f i l m p r e p a r a t i o nT h e d i f f e r e n t P C P - E R L g e l s w e r e p o u r e d i n t o

P e t r i d i s h e s a n d d r i e d a t 5 0 C u n t i l a f i l m (1 2 0 -1 5 0~ m t h i c k ) w a s fo rm e d ( a p p ro x . 2 4 h ) .

2 . 3. S w e l l i n g s t u d i e sTh e s w e l l i n g p ro p e r t i e s o f t h e P C P -ER L f i l m s

w e r e m e a s u r e d g r a v i m e t r i c a l l y b y s o a k i n g e a c h i nP B S , p H = 5 a n d p H = 7 . 4 u n t il e q u i li b r iu m ( - 4 h )a n d c o m p a r i n g t h e i r w e t a n d d ry w e i g h t s ( e x p re s s e di n p e r c e n t ) .2 .4 . T o r s i o n f o r c e m e a s u r e m e n t s

Th e t o r s i o n fo r c e o f t h e s w o l l e n P C P -E R L f i lm s a ts t e a d y s t a t e w a s m e a s u re d u s i n g a t o r s i o n b a l a n c e .Th e s w o l l e n f i l m s w e re m o u n t e d b e t w e e n t w o c l i p s ,o n e o f w h i c h w a s m o v a b l e . A g r a d u a l f o r c e w a so p e ra t e d b y a d d i n g w e i g h t s a t a c o n s t a n t r a t e a n d t h ef i l m t o r s i o n ( i n g r a m - fo rc e ) w a s m e a s u re d a t t h eb re a k i n g p o i n t o f t h e f i l m s .

2 .5 . M o d u l u s o f e la s t ic i t y m e a s u r e m e n tTh e f i l m s ' m o d u l u s o f e l a s t i c i t y a t s w o l l e n s t a t e

(P B S , p H -~ 7 .4 , u n t i l s t e a d y s t a t e ) w a s m e a s u re da c c o rd i n g t o t h e m e t h o d d e s c r i b e d b y C l u f f e t a l .[14 ] . Br ie f ly , the swol len f i lm was in ser ted in to a1 0 -m l p l a s t i c s y r i n g e o n t h e t o p o f w h i c h p r e s s u rew a s g r a d u a l l y o p e ra t e d u n t i l m a x i m a l c o n d e n s a t i o nw a s a c h i e v e d . T h e m o d u l u s o f e l a s t i c it y w a s c a l c u -l a t e d a c c o rd i n g t o t h e fo l l o w i n g e q u a t i o n :F - G o , ~ - a - 2 ) (1 )Aw h e re F i s t h e t e n s i o n fo r c e , A is t h e s u r f a c e a r e a o ft h e c y l i n d e r , ) t i s t h e p ro d u c t o f t h e h y d ro g e l v o l u m eb e fo re a n d a f t e r p r e s s i n g t h e g e l a n d G O i s t h em o d u l u s o f e l a s ti c i ty . G o i s c a l c u l a t e d f ro m t h eFl i n e a r s l o p e o f ~ - vs . - - 2 .

2 . 6 . T a b l e t p r e p a r a t i o nP C P -ER L m i x t u re s c o n t a i n i n g i n c r e a s i n g a m o u n t s

o f E R L w e r e p r e p a r e d a s d e s c r i b ed a b o v e . F i lm sw e re p r e p a re d , d r i e d , c o m m i n u t e d a n d l y o p h i l i z e d .Th e f i n a l c o n c e n t r a t i o n s ( w / w ) o f ER L i n t h em i x t u re s w e re : 0 , 5 , 2 0 a n d 5 0 . Th e p o w d e re dm i x t u re s w e re c o m p re s s e d (1 t o n ) i n t o 5 0 0 m gt a b l e t s u s i n g a P e rk i n E l m e r m a n u a l p r e s s . Th ec ru s h i n g s t r e n g t h (D r . K . S c h l e u i n g e r a n d C o . ,m o d e l 2 E / 2 0 5 , S w i t z e r l a n d ) o f t h e t a b l e t s r a n g e df ro m 6 t o 9 k g R d e p e n d i n g o n t h e r e l a t i v e c o n t e n t so f E R L . T h e h i g h e r th e a m o u n t o f E R L , t h e w e a k e rtab le t ob ta ined .2 . Z E r o s i o n m e a s u r e m e n t

T a b l e t s o f 5 00 m g w e r e p l a c e d in 5 0 0 m l o f P B S( p H = 7 . 4 ) i n a pa d d l e U . S . R t y p e I I d is s o lu t io na p p a ra t u s (V a n k e l V K 7 0 0 0 , U S A ) a t 3 7 C . Th ep a d d l e s w e re ro t a t e d a t 1 0 0 r e v . / m i n , a r a t e w h i c h i se x p e c t e d t o c o r r e l a t e w i t h t h e e ro s i o n r a t e t a k i n gp lace in the GI t rac t o f the dog [15] . A t p re-d e t e rm i n e d t i m e i n t e rv a l s a w h o l e s i n g l e t a b l e t w a sw i t h d ra w n , d r i e d (6 0 C fo r 2 h , f o l l o w e d b y 1 0 0 Cfo r 2 4 h ) , a n d w e i g h e d . Th e r e t a i n e d w e i g h t w a se x p re s s e d a s p e r c e n t o f i n i t i a l w e i g h t .2 . 8. T a b l e t p r e p a r a t i o n f o r m u c o a d h e s i o n s t u d i e s

P C P - E R L p o w d e r e d m i x t u r e s , c o n t a i n i n g i n c r e a s -i n g a m o u n t s o f ER L, w e re p r e p a re d a s d e s c r ib e da b o v e . Th e f in a l c o n c e n t r a t i o n s ( w / w ) o f ER L i nthe mix tu res were : 0 , 5 , 10 , 20 and 75 . The mix tu resw e re c o m p re s s e d (5 t o n ) i n t o 1 0 0 -m g d i s c s u s i n g aP e rk i n E l m e r m a n u a l p r e s s . Th e d i s c s w e re g l u e d t oa p o l y p ro p y l e n e s u r f a c e , b a l a n c e d t o a t o t a l w e i g h to f 5 g a n d a l l o w e d t o s w e l l in P B S , p H = 7 fo r 1 0m i n [ 1 6] .2 . 9 . M u c o a d h e s i o n s t u d i e s

In t e s t in a l t i ss u e s ( s t o m a c h , j e j u n u m , c e c u m a n dp ro x i m a l c o l o n ) f ro m p re v i o u s l y s a c r i f ic e d S a b ra r a t sw e re s p r e a d a n d m o u n t e d o v e r a P e t r i d i s h c o n -t a i n in g e i t h e r o f t he b u f f e r s . Th e s w o l l e n p o l y m e r sw e re p l a c e d s e p a ra t e l y o n t h e t i s su e s fo r 2 m i n . Th e nt h e p o l y p ro p y l e n e s u r f a c e w h i c h w a s d i r e c t e d u p w a s


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60 B. Tirosh et al. / Journal of Controlled Release 45 1997) 57- 64c o n n e c t e d t o a f o rc e g a u g e ( 2 5 0 m g a c c u r a c y ) w h i c hw a s l i f t e d a t a c o n s t a n t r a t e . Th e a d h e re n c e fo r c ew a s d e t e rm i n e d a t t h e t i m e o f d e t a c h m e n t a n d t h ew e i g h t o f t h e p o l y p ro p y l e n e s u r f a c e w a s s u b t r a c t e d[1 6 ] . Ea c h s t u d y w a s r e p e a t e d fo u r t i m e s .

a c id , p H = 2 . 2 a n d 5 0 v / v a c e t on i tr il e , R . T . ~ 5 . 6m i n , a t 2 7 3 n m ) i n t h e w i t h d ra w n s a m p l e s .

3 R e s u l t s

2.10. Cefazolin an d cefazolin ibuprofen tabletpreparat ion and drug release s tudiesTh e o b j e c t i v e o f th i s s t a g e w a s t o e x a m i n e

w h e t h e r P C P - E R L c o m p r e s s e d t a b l e t s a r e a b l e t os y n c h ro n i z e t h e r e l e a s e r a t e o f t w o p ro b e s d i f f e r i n gf ro m e a c h o t h e r b y t h e i r s o l u b i l i ty p ro p e r t i e s: s o d i u mc e fa z o l i n (C EF , h i g h l y w a t e r s o l u b l e ) a n d i b u p ro fe n( IB U , l o w w a t e r s o l u b i l i t y ) . Th e s t u d y w a s d i v i d e di n t o t w o s t e p s : ( a ) c o m p a r i s o n b e t w e e n t h e r e l e a s ek i n e t i c s o f C E F f r o m P C P - E R L t a b l e t s a n d t h ee ro s i o n k i n e t i c s o f th e s e t a b l e t s, ( b ) c o m p a r i s o nb e t w e e n t h e r e l e a s e k i n e ti c s o f C E F a n d I B U f r o mP C P - E R L t a b l e t s .

I n t h e f i r s t c a s e 2 0 m g o f C EF w a s m i x e d w i t h1 75 m g o f P C R 1 75 m g o f E R L a n d 1 30 m g o fm a n n i t o l . I n th e s e c o n d c a s e 4 0 m g o f C EF a n d 4 0m g o f I B U w e r e m i x e d w i t h 1 7 5 m g o f P C R 1 75 m go f E R L a n d 7 0 m g o f m a n n i to l . T a b l e ts , 5 0 0 m ge a c h, w e r e c o m p r e s s e d a s m e n t i o n e d a b o v e t o g i v eP C P - E R L c e f a z o l i n t a b l e t s ( C E F t a b l e t s ) a n d P C P -E R L c e f a z o l i n / i b u p r o f e n t a b l e t s ( C E F / I B U t a b l e t s ) .M a n n i t o l w a s a d d e d t o a c h i e v e c o n t ro l o v e r t h et a b l e t s ' p o ro s i t y a n d , h e n c e , t h e i r s w e l l i n g a n dd e g ra d a t i o n p ro p e r t i e s , t o r e l e a s e a s m u c h d ru g a sp o s s i b l e w i t h i n 4 h , a p e r i o d o f t i m e w h i c h i sr e q u i r e d fo r s o l i d d o s a g e fo rm s i n t h e s m a l l b o w e l[17].

Th e d i s s o l u t i o n t e s t s w e re c o n d u c t e d a c c o rd i n g t ot h e p r o c e d u r e m e n t i o n e d a b o v e . A t p r e d e t e r m i n e dt i m e i n t e rv a l s 5 -m l s a m p l e s w e re w i t h d ra w n fo rd ru g ( s ) a n a l y s i s a n d r e p l e n i s h e d w i t h t h e s a m ev o l u m e o f f r e s h b u f f e r s o l u t i o n .

H P L C ( H e w l e t t P a c k a r d 1 0 50 p u m p i n g s y s te m ,J a s c o 8 7 5 In t e l l i g e n t U V / V i s d e t e c t o r ) w a s u s e d t oa s s a y s e p a ra t e l y th e C EF ( c o l u m n : L i C h ro s p h e r 1 00 ,R P - 1 8 , 5 t x m , 2 5 c m 4 r a m , M e r c k , G e r m a n y ) ,f l o w ra t e : 1 .5 m l / m i n , m o b i l e p h a s e : s o d i u m a c e t a t e0 .0 1 M , p H = 5 . 2 8 6 v / v , 1 3 . 6 v / v a c et o n it r il e ,0 . 4 v / v m e t h a n o l , R .T . ~ 3 .2 m i n , d e t e c t io n a t 2 6 2n m ) a n d t h e IB U ( c o l u m n : a s a b o v e ) f l o w r a t e : 1 . 5m l / m i n , m o b i l e p h a s e: 5 0 v / v d i l u te p h o s p h o ri c

Th e k i n e t i c s o f f l u i d u p t a k e o f P C P -ER L f i l m s i nt w o b u f f e r s o lu t io n s , P B S , p H = 7 . 4 ( t y p ic a l o f t h ea v e ra g e p H v a l u e o f t h e s m a l l i n t es t in e ) a n d P B S ,pH = 5 .0 (c lose to the p H in the l a rge in tes t ine) a res h o w n i n F ig . 1 . A l t h o u g h t h e r e w a s l e s s i n t h e l o w e rp H c o n d i t i o n s , i n b o t h c a s e s t h e r e w a s a p ro fo u n dd i f f e r e n c e b e t w e e n t h e s w e l l i n g o f p u re P C P f i l m sa n d f i l m s m a d e o f m i x t u r e s o f P C P a n d i n c r e a s i n ga m o u n t s o f ER L . T h e ER L w a s a b l e to s i g n i fi c a n t lyd e c re a s e t h e s w e l l i n g o f P C P f i lm s i n a c o n c e n t r a t io nd e p e n d e n t m a n n e r . T h e i n c o r po r a t io n o f E R L i n toP C P a l s o a f f e c t e d th e m e c h a n i c a l p ro p e r t i e s o f th ef i l m s , a s w a s e v i d e n t f r o m t h e t o r s i o n fo r c e m e a s u re -m e n t s (F i g . 2 ) a n d t h e m o d u l u s o f e l a s ti c i t y (Ta b l e1 ) . Th e h i g h e r t h e a m o u n t o f ER L i n t h e m i x t u r e s

125100v

= 5025

0

A

S = r. ~ ~ No ERL5% ERLa 10% ERLi 50% ERLre'am-- 75% ERL

i r i i f50 100 150 200 250Time, minutes

2520

.~ 1510'~ 5

00

r . ~ ~ No ERL5% ERLI0% ERL20% ERL50% ERL75% ERLi i r i50 100 150 200 250

Time, minutesFig. 1. Fluid uptake kinetics of PCP-ERL films in PBS, pH=7.4(A) and PBS, pH=5.0 (B). The mean values of six measurements_+S.D. are shown.


5/8

B . T i r o sh e t a l . / J o u r n a l o f C o n t r o l l e d R e l e a s e 4 5 1 9 9 7 ) 5 7 - 6 4 61

, . ~ 3 0o 2 5

2 i 1 5 i

1 0

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0w / w o f E R L i n th e f il m

Fig. 2. The dependency of the torsion force of PCP-ERL fihns atswollen state on the ERL concentration in the films. The meanvalues of six measurements +_S.D. are shown.

w i th t h e P C R th e l a r g e r th e v a lu e s o f t o r s io n f o r c ea n d mo d u lu s o f e l a s t i c i t y .I n t h e e r o s io n s tu d ie s d i f f e r e n t r e su lt s w e r e o b -

t a in e d w h e n t a b l e t s o f P C P a n d i n c r e a s in g a m o u n t so f E R L w e r e t e st e d in P B S b u f f e r , p H = 7 . 4 ( F ig . 3 ) .I n t h e c a se o f t h e t a b l e t s , t h e h ig h e r t h e a mo u n t o fE R L th e l a r g e r t h e r a t e o f e r o s io n o f t h e t a b l e t ,l e a d in g t o f a s t e r d i s i n t e g r a t i o n o f t h e P C P - E R Ltable ts . I t appea rs tha t , in cont ra s t to the re su l t so b t a in e d w i th t h e f i lms w h e r e i n c r e a s in g a mo u n t s o fE R L s t a b i l i z e d t h e me c h a n ic a l p r o p e r t i e s o f t h ef i lms , t h e a d d i t i o n o f E R L to P C P t a b l et s i n t e r f e r e dw i th t h e c o h e s io n b e tw e e n t h e P C P p a r t i c l e s , r e d u c -in g t h e c o mp r e s s ib i l i t y o f t h e mix tu r e s , t h u s mo r ee r o d ib l e t a b l e t s w e r e o b t a in e d .

F ig . 4 sh o w s th e ma tc h in g b e tw e e n t h e e r o s io nr a t e o f P C P - E R L t a b l et s ( a l so c o n t a in in g ma n n i to l t oa c c e l e r a t e t h e e r o s io n r a t e o f t h e t a b l e t s ) a n d t h er e l e a se r a t e o f t h e w a te r so lu b l e d r u g C E F f r o m C E Ftable ts , ind ica t ing tha t , p r ior to i t s degrada t ion , thema t r i x sw e l l i n g p r o c e s s i n t e r r u p t s t h e d i f f u s io n o fC E F . T h e o v e r a l l r e su l t i s sy n c h r o n i z a t i o n b e tw e e nth e tw o p r o c e s se s . T h i s o b se r v a t i o n w a s v e r i f i e d b yth e s tu d y p e r f o r me d w i th t a b l e t s c o n t a in in g C E F a n dTable 1

100 ~90so.= 70~ 605 04 03 3o,2 0

i 00

5% ERLr~ 20% ERL 50% ERL

' i , . t , J . i , , , i , L , I , i , ,

30 60 90 120 150 180 210 240 270 300 330 360Time, minutes

Fig. 3. The erosion rates of PCP-ERL tablets containing increasingamounts of ERL in PBS buffer (pH=7.4).

120100 o % Drug release . / ~

80 ~ l~. 60

4o2O

> O

0 60 120 180 240 300 360Time, m inutesFig. 4. The release kinetics of sodium cefazolin from CEF tablets(expressed as % cumulative release) and the erosion kinetics ofCEF tablets (expressed as % erosion of initial weight), demon-strating similar kinetic rates. The mean values of six measure-ments +_S.D. are shown.

I B U ( C E F / I B U t a b l e t s ) . A s c a n b e s e e n i n F ig . 5 ,the two drugs were re leased a t s imi la r r a te s , ind ica t -ing tha t tab le t e ros ion ( lead ing to the re lease ofib u p r o f e n ) o c c u r r e d p a r a l le l t o t h e d i f f u s io n o f C E F .

F ig . 6 su mma r i z e s t h e mu c o a d h e s io n p r o p e r t i e so f m a t r i x t a b l e t s m a d e o f m i x t u r e s o f P C P w i t hin c r e a s in g a mo u n t s o f E R L . I n t h i s s e c t i o n o f t h es tu d y t h e mu c o a d h e s io n p r o p e r t i e s o f t h e v a r io u sty p e s o f P C P - E R L t a b l e t s t o d i f f e r e n t r e g io n s o f t h e

The modu lus of elasticity (Go) of swoll en (PBS, pH = 7.4) PCP-ERL films, containing increasing amounts of ERL, at steady stateParameter Concentration (% w/w ) of ERL in the PCP-ERL film

0 5 10 20 50 75G 1272 2041 5302 5941 6561 18190R 0.991 0.955 0.983 0.979 0.973 0.999The values are the mean of six different measurements. To each Go-value is attached its linear regression value (R).


6/8

62 B. Tirosh et al. / Journal of Controlled Release 4 5 1997) 57- 64. - , 110~100 .90 -8 07 06 0, ~ 5 040 -'~ 30 :20 -10~0 0

To Sod .cefazo lin / . ~

i J i i i i

60 120 180 240 300 360Time, minutesFig. 5. The release kinetics of sodium cefazolin and ibuprofenfrom CEF/IBU tablets, demonstrating similar release rates of thehighly soluble ( so diu m cefazolin) mad the sp aringly soluble(ibuprofen) drug molecules from the erodible matrices. The meanvalues of six m easurem ents _+S.D. are show n.G I t r a c t o f th e r a t w e r e e x a m i n e d . I t w a s f o u n d t h a ta l l ty p e s o f t a b l e t s a d h e r e d s i g n i f i c a n t l y b e t t e r to t h ec e c u m o f t h e r a t a n d t h a t t h e i r a d h e r e n c e t o t h es t o m a c h , j e j u n u m a n d c o l o n d i d n o t d i ff e r f r o m e a c ho t h e r . T h e s e r e s u l t s v e r i f y a p r e v i o u s r e p o r t [ 1 6 ] i nw h i c h i t w a s f o u n d t h a t t he r a t c e c u m p o s s e s s e s t h eb e s t m u c o a d h e s i o n p r o p e r t i e s w h e n t e s t e d w i th P C Pd i s c s. A s f a r a s th e e f f e c t o f E R L o n t h e a d h e r e n c ep r o p e r t i e s w a s c o n c e r n e d , F i g . 6 s h o w s t h a t f o r m u l a -t i on s t h a t c o n t a i n e d u p t o 2 0 w / w o f E R L b e h a v e ds i m i l a r l y i n t e rm s o f m u c o a d h e s i o n t o th e G I e p i -t h e li u m . E R L c o n c e nt r a ti o n s o f 5 0 w / w a n d a b o v es i g n i f i c a n t l y r e d u c e d t h e a b i l i t y o f t h e d i s c s t o a d h e r et o t h e G I e p i t h e l i u m . I n f a c t , r e s i d u a l m u c o a d h e s i o np r o p e r t i e s w e r e d e t e c t e d i n th e j e j u n u m , w h i l e i n t h e

3 .02.52.0

g 1.5..= ].0-= 0 . 5E 0 . 0

[ ] No ERL[] 5 ERL[] 10 ERL[] 20 ERL[] 50 ERL[] 75 ERL ~

tomach Jejunum Cecum ColonFig. 6. The mucoadhesion properties of PCP -ER L discs withelevated amounts of ERL as m easured on the epithelium of fourregions in the G I tract of the rat . The m ea n values of fourmeasurements -+S.D. are shown.

r e s t o f th e G I o r g a n s t h i s e f f e c t w a s a l m o s t d i -m i n i s h e d .

4 . D i s c u s s i o n

I n t h i s s t u d y w e s h o w e d t h a t P C P c o u l d b ef o r m u l a t e d i n t o t w o t y p e s o f s o l i d d o s a g e f o r m s ,f i l m s a n d c o m p r e s s e d t a b l e t s . I n b o t h c a s e s t h ea d d i t i o n o f a h y d r o p h o b i c p o l y m e r i s r e q u i re d t oa c h i e v e a c o n t r o l o v e r t h e r e m a r k a b l e s w e l l i n g ( i nt h e c a s e o f f il m s ) a n d c o m p r e s s i o n ( i n th e c a s e o ft a b le t s ) p r o p e r t i e s o f P C R T h e a d j u v a n t p o l y m e rw h i c h w a s u s e d i n th e s t u d y w a s E u d r a g i t R L - 1 0 0( E R L ) , a c o p o l y m e r o f a c r y li c a n d m e t h a c r y l i c a c i de s t e rs w i t h a l o w c o n t e n t o f q u a t e r n a r y a m m o n i u mg r o u p s . E R L d o e s n o t d i s s o l v e i n w a t e r a n d c a n f o r me l e c t r o s t a ti c b o n d s w i t h t h e c a r b o x y l g r o u p s o f P C P .T h e s e b o n d s c r e a t e a p h y s i c a l c r o s s l i n k in g b e t w e e nt h e P C P c h a i n s s o t h a t th e n e t n e g a t i v e c h a r g e o f t h eh y d r o g e l is a t t e n u a t e d i n a m a n n e r w h i c h a f f e c t s i tss w e l l i n g o r c o m p r e s s i o n p r o p e r t i e s. E R L w a s a b l e tod e c r e a s e t h e s w e l l i n g p ro p e r t i e s o f P C P f i lm s i n t w ob u f f e r s o l u t io n s ( p H = 7 . 4 a n d p H = 5 ) ( F i g . 1 ), t oi n c r e a s e t h e s t e a d y s t a t e t o r s i o n f o r c e p r o p e r t i e s o fP C P f i lm s ( F i g . 2 ) a n d t o in c r e a s e t h e m o d u l u s o fe l a s t i c i t y o f P C P i n s w o l l e n s t a t e ( T a b l e 1 ) i n ac o n c e n t r a t i o n - d e p e n d e n t m a n n e r . I t h a s b e e n p r e v i -o u s l y s h o w n [ 1 1] t h a t i t i s a l m o s t i m p o s s i b l e toa c h i e v e p u r e P C P f i lm s t h a t w o u l d m a i n t a i n t he i ri n t e g r i t y f o r a r e a s o n a b l e p e r i o d o f t im e i n t h e f lu i d so f t h e G I t r a c t . T h e f i n d i n g s o f t h i s s t u d y s u g g e s tt h a t s o u n d f i lm s c o u l d b e f a b r i c a t e d fr o m m i x t u r e s o fP C P a n d E R L i n w h i c h s w e l l i n g p ro p e r t i e s c o u ld b eb a l a n c e d b y m o d i f y i n g t h e a m o u n t s o f E R L i n t h ef i l m s .

I n v e r s e b e h a v i o r o f E R L w a s e x p e c t e d i n c o m -p r e s s e d t a b l e ts o f P C E S i n c e t h e l a t te r i s e x t r e m e l yc o m p r e s s i b l e , t h e f o r m e r s e r v e s a s a d e c o m p r e s s i n ga d j u v a n t a i m e d a t i n c r e a s i n g t h e d i s i n t e g r a t i o n r a t eo f P C P t a b l e t s . I t w a s f o u n d t h a t t h e h i g h e r t h ea m o u n t o f E R L i n th e t a b l e ts t h e f a s te r t he e r o s i o nr a t e o b s e r v e d ( F i g . 3 ) , a n d i t c a n b e c o n c l u d e d t h a t,i n th e c a s e o f P C P - E R L t a b le t s , e r o s i o n r a te c o u l d b eb a l a n c e d b y m o d i f y i n g t h e a m o u n t s o f E R L i n t h et a b l e t s .

T h e a b i l i ty t o r e g u la t e t h e e r o s i o n r a t e o f P C P -E R L t a b l e ts w a s e x p l o i t e d to g a i n c o n t r o l o v e r t h e


7/8

B . T i r o s h e t a l . / J o u r n a l o f C o n t r o l l e d R e l e a s e 4 5 1 9 9 7 ) 5 7 - 6 4 63re l e a s e r a t e o f t w o d ru g p ro b e s f ro m t h e t a b l e t s , t h eh i g h l y w a t e r s o l u b l e s o d i u m c e fa z o l i n (C EF ) a n d t h es p a r i n g l y w a t e r s o l u b l e i b u p ro fe n ( IB U ) . I t w a sd e m o n s t r a t e d t h a t t a b l e t s m a d e o f e q u a l a m o u n t s o fP C P a n d ER L ( t o g e t h e r w i t h m a n n i t o l t o i n c r e a s ep o ro s i t y ) w e re a b l e t o r e l e a s e a t s i m i l a r r a t e s( ' s y n c h r o n i z e d r e l e a s e ' ) t h e t w o d r u g m o l e c u l e s(F i g . 5 ) . Th e r e a s o n fo r t h e s i m u l t a n e o u s r e l e a s e o fd ru g m o l e c u l e s p o s s e s s i n g d i f f e r e n t p h y s i c o -c h e m i -c a l p ro p e r t i e s i s t h e d i r e c t i o n a l i z e d e ro s i o n p ro c e s so f th e P C P - E R L t a b l e ts . F r o m t h e m a t c h i n g b e t w e e nt h e t a b l e t s ' e ro s i o n a n d d ru g r e l e a s e r a t e s , a s s h o w nin F ig . 4 , i t can be conc luded tha t , ra ther than f reed ru g d i f fu s i o n , t h e C EF r e l e a s e w a s g o v e rn e d b y t h emat r ix e ros ion . I t i s reasonab le to specu la te tha t , int h e c a s e o f C EF , t h e r e l e a s e p ro c e s s i n v o l v e s t w os i m u l t a n e o u s p ro c e s s e s : ( a) s w e l l i n g o f t h e p o l y m e r i cm a t r i x w h i c h i n t e r f e r e s w i t h t h e d ru g d i f fu s i o n , a n d(b ) c o l l a p s e o f t h e s w o l l e n p o l y m e r , l e a d i n g t o t h eC E F d i f fu s i o n o u t o f t h e d ru g c a n 'i e r . Th e c a r r i e r ' sc o l l a p s e ( e ro s i o n ) i s t h e s o l e r e a s o n fo r t h e IB Ure l e a s e . A p ro p e r b a l a n c e o f th e P C P a n d ER L r a t i o sl e d to t h e s y n c h ro n i z e d r e l e a s e o f t he C E F a n d IB Uas demons t ra ted in F ig . 5 .

Th e f i n d in g s o f t h e s t u d y p r e s e n t e d h e re i m p l y t h a tP C P -ER L s o l i d d o s a g e fo rm s , o r s i m i l a r b l e n d s ,c o u l d b e u s e d t o d e l i v e r d ru g m o l e c u l e s t o t h e G It r a c t a n d r e l e a s e t h e m i n p r e d e t e rm i n e d r a t e s a c c o m -p a n i e d b y m o l e c u l e s o f d i f f e r e n t p h y s i c o - c h e m i c a ln a t u r e . Th e i m m e d i a t e a s s o c i a t i o n i s p e p t i d e d ru g s .S u c c e s s fu l o r a l a d m i n i s t r a t io n o f a p r0 t e in a c e o u sd ru g u s u a l l y c a l l s f o r a c o n s t a n t p r e s e n c e o f p ro t e a s ei n h i b i t o r a n d a b s o rp t i o n e n h a n c e r i n t h e v i c i n i t y o fthe abso rp t ion s i t es . Th is p rerequ is i t e i s d i f f i cu l t tom e e t a n d i n m a n y c a s e s a l l f o r m u l a t i o n c o m p o n e n t sa r e p a c k e d i n a d o s a g e fo rm s u c h a s a c o n v e n t i o n a lg e l a t i n c a p s u l e w h i c h d i s s o l v e s r a p i d l y a n d e x p o s e si t s con ten t s to the l a rge d i lu t ion e f fec t in the GI t rac t .B e c a u s e o f d i f f e r e n t w a t e r s o l u b i l it i e s t h is c o u l d l e a dto a s i tua t ion in wh ich the p ro te inaceous d rug i s l e f tw i t h n o p ro t e c t i o n o r a b s o rp t i o n a i d s . A t r i v i a ls o l u t i o n w o u l d b e t h e u s e o f o s m o t i c p u m p t e c h n o l o -g y w h i c h e n a b l e s t h e r e l e a s e o f d ru g s i n a z e ro o rd e rk i n e t i c s . A s i m p l e a l t e rn a t i v e c o u l d b e t h e u s e o f ap r o p e r l y d e s ig n e d e r o d i b l e p o l y m e r s u c h a s t h e P C P -ER L t a b l e t s p r e s e n t e d h e re .

P C P -ER L c a r r i e r s a r e p o t e n t i a l l y a d v a n t a g e o u s fo rt h e o r a l d e l i v e ry o f p ro t e i n a c e o u s d ru g s b e c a u s e o f

t w o a d d i t i o n a l i m p o r t a n t r e a s o n s : ( a ) Th e y c a nre l e a s e c o n s t a n t a m o u n t s o f P C P o v e r ti m e . A s w a sp r e v i o u s ly r e p o r te d [ 4 - 7 ] P C P p o s s e s se s p r o t e a s ei n h i b i t i o n a n d a b s o rp t i o n e n h a n c e m e n t p ro p e r t i e s .Th e re fo re , t a b l e t s o r f i l m s t h a t c o n t a i n P C P a s afu n c t i o n a l a d j u v a n t a r e a b l e t o d i s t r i b u t e P C P a l o n gt h e G I t r a c t i n a c o n t ro l l e d m a n n e r s o t h a t c o n s t a n tP C P p ro t e c t i o n a g a i n s t p ro t e o l y t i c a c t i v i t y a n d a b -s o rp t i o n e n h a n c e m e n t i s a c h i e v e d . ( b ) P C P i s w e l lr e c o g n i z e d fo r i t s m u c o a d h e s i o n p ro p e r t i e s [ 1 3 ] .P C P - E R L t a b l e t s ( c o n t a i n i n g u p t o 2 0 w / w o fER L ) w e re fo u n d t o a d h e re t o t he e p i t h e l i u m o f t h eG I t r a c t o f t h e r a t a s w e l l a s p u re P C P d i s c s (F i g . 6 ) .Th e b e s t a d h e re n c e w a s o b s e rv e d i n t h e c e c u m ,ver i fy ing a p rev ious s tudy [10 ] and ind ica t ing tha tt h e c o l o n , b e c a u s e o f it s t h in n e r m u c u s l i n i n g , m a yb e t h e p r e f e r r e d o rg a n fo r m u c o a d h e s i o n o f s u c hd o s a g e fo rm s . Th e i n t i m a t e c o n t a c t b e t w e e n t h ep o l y m e r i c c a r r i e r a n d t h e G I e p i t h e l i u m s h o r t e n s t h ed i f fu s i o n a l p a s s t o w a rd s t h e s i t e o f a b s o rp t i o n a n dk e e p s c o n s t a n t l e v e l s o f s w o l l e n P C P a t t h a t p r e c i s eloca t ion .

5 C o n c l u s i o n s

ER L w a s fo u n d t o b e a c o n c e n t r a t i o n -d e p e n d e n tr e g u l a t i n g a g e n t i n P C P s o l i d d o s a g e fo rm s . I n c r e a s -i n g a m o u n t s o f E R L i m p r o v e d t h e m e c h a n i c a lp ro p e r t i e s o f P C P f i l m s a n d i n c r e a s e d t h e d e g ra -d a t i o n r a t e o f P C P t a b l e t s . Th e a b i l i t y o f P C P -ER Ls o l i d c a r r i e r s t o s y n c h ro n i z e t h e r e l e a s e r a t e o f C EFa n d IB U , a n d t h e u n i q u e p ro p e r t i e s o f P C P , n a m e l yi t s m u c o a d h e s i o n , e n z y m e i n h i b i t i o n a n d a b s o rp t i o ne n h a n c e m e n t p ro p e r t i e s , s u g g e s t t h a t t h e y m a y b es u i t ab l e fo r t h e o r a l d e l i v e ry o f p ro t e i n a c e o u s d ru g s.H o w e v e r , t h e e f f e c t o f e l e v a t e d c o n c e n t r a t i o n s o fER L o n t h e e n z y m e i n h i b i t i o n a n d a b s o rp t i o n e n -h a n c e m e n t p ro p e r t i e s o f P C P n e e d s t o b e i n v e s t i -g a t e d . I t i s c u r r e n t l y b e i n g e x a m i n e d i n o u r l a b o ra -to ry .

6 N o t a t i o n

P C P = p o l y c a r b o p h ilE R L = E u d r a g i t R L - 1 0 0C E F = s o d i u m c e f a z o li n


8/8

6 4 B. Tirosh et al. / Journal of Controlled Release 45 1997) 57- 64I B U = i b u p r o f e nC E F t a b l e t s = t a b l e ts m a d e o f a m i x t u r e o f P C P , E R La n d m a n n i t o l c o n t a i n in g 2 0 m g o f so d i u m c e f a z o l i nC E F / I B U t a b l e t s = T a b l e t s m a d e o f a m i x t u r e o fP C R E R L a n d m a n n i t o l c o n t a in i n g 4 0 m g o f s o d i u mc e f a z o l i n a n d 4 0 m g o f i b u p r o f e np o l y ( H E M A ) = p o l y ( h y d r o x y e t h y l m e t h a c r y l i c a c id )

cknowledgmentsT h e w o r k w a s s u p p o r t e d b y a r e s e a r c h g r a n t

( 4 5 5 0 ) f r o m t h e J o i n t R e s e a r c h C e n t e r o f t h e E CC o m m i s s i o n f o r S c i e n c e a n d R D a n d th e Is r a e l iM i n i s t r y o f S c i e n c e a n d A r t s .

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Effect of Eudragit on the Mechanical and Mucoadhesion Properties of Polycarbophil Dosage Forms

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