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In ternat iona l Journa l o f Pharmaceutics , 5 4 ( 1 9 8 9 ) 1 7 5 - 1 7 9 1 7 5E ls e v ie r

I JP 01853

In c lu s io n o f r e t in o ic a c id in f l c y c lo d e x tr inDidja Am didouch e 1, Henri Darrouzet 2 Dominiq ue DuchSne 3 and Marie-Christine Poelman 1

I Ddp artem ent de Dermopharmacie, Facultd de Pharmacie, Universitd de Paris V, Paris France), e Socidtd Roq uette Frbres,Les t rem France) , 3 Laboratoi re de Pharmac ie Galdnique e t Biopharmacie, UA C N R S 1218, Facult~ de Pharmacie ,

Univers itd de Par i s XI , Ch~tenay M alabry France)( Re c e iv e d 6 De c e mb e r 1 9 8 8)

( M o d i f i e d v e r s io n re c e iv e d 1 5 M a r c h 1 9 8 9 )( Ac c e p te d 2 0 M a r c h 1 9 8 9 )

Key words: fl-Cyclodextrin; Inclusion; Retinoic acid; SolubilitySummary

Re t in o ic a c id i s w id e ly u s e d in d e r ma to lo g y . I t s u s e i s, h o we v e r , l imi t e d b y a n u m b e r o f d r a wb a c k s , in c lu d in g i t s in s o lu b i l i ty ina q u e o u s v e h i cl e s. T h e i n c l u s i o n o f t h i s c o m p o u n d i n f l -c y c l o d ex t r in w o u l d a p p e a r t o r e d u c e s o m e o f t h e d r a w b a c k s . T h e p r o c e d u r ea d o p t e d f o r t h e p r e p a r a t i o n o f t h e i n c l u s io n w a s c o p r e c i p i ta t i o n f r o m a w a t e r / i s o p r o p a n o l e q u i m o l e c u l a r s o l u t i o n o f f l -c y c l o de x t r ina n d r e t in o ic a c id , s t ir r e d f o r 1 6 d a y s a t l o w t e m p e r a tu r e ( 6 o C) , a n d s h ie ld e d f r o m l ig h t . Th e in c lu s io n i s id e n t i f i e d b y s c a n n in ge le c t r o n mic r o s c o p y , c i r c u la r d i c h r o i s m, d i f f e r e n t i a l s c a n n in g c a lo r ime t r y , a n d X - r a y d i f f r a c t io n p a t t e r n s . Th e a q u e o u s s o lu b i l i ty o fr e t in o ic a c id , wh ic h i s l e s s th a n 0 . 5 mg /1 f o r th e p u r e p r o d u c t , i n c r e a s e s to 1 2 r a g /1 f o r th e p h y s ic a l mix tu r e , a n d r e a c h e s 1 6 0 mg /1f o r th e in c lu s io n .

I n t r o d u c t i o nThe enhancement of the therapeutic interest of

retinoic acid and of whole retinoids has beenconsiderable during the past few years (Saurat,1985).

In dermatology, they improve cicatrization byan increase in collagen synthesis. In the treatmentof acne, the topical administration of retinoic acidhas a keratolytic activity which contributes to theelimination of microcysts and comedones. Fur-thermore, it stimulates the follicular epitheliumand free keratinocyte proliferation, which are then

Correspondence: D . D u c h ~ n e , L a b o r a t o i r e d e P h a r m a c i eG a l r n i q u e e t B i o p h a r m a c i e , F a c u l t 6 d e P h a r m a c i e , U n i v e r s i t 6d e P a r i s X I , R u e J e a n B a p t i s t e C l r m e n t , 9 2 2 9 6 C h f t t e n a yM a l a b r y C r d e x , F r a n c e .

carried away by the sebum flow (Kligman et al.,1969). More recently, topical retinoic acid hasbeen proposed for its favourable effect on epider-mal growth and action on keratinization in thetreatment of epidermal dysplasia and photo-age-ing (Connor et al., 1986; Weiss et al., 1988).

Unfortunately, a number of drawback limitsthe use of this drug: its insolubility in aqueousmedium, its poor stability in the presence of airand light, and, on the other hand, its local irritat-ing reaction, and the low cutaneous tolerance itinduces (Lehman et al., 988).

For their part, cyclodextrins, and the mostcommonly-available, fl-cyclodextrin, are well-known for their ability to form inclusion com-pounds with a large number of molecules, amongwhich are found slightly hydrosoluble pharmaceu-tical active ingredients. The inclusion results in a

0 3 7 8 - 5 1 7 3 /8 9 / 0 3 . 5 0 1 9 8 9 E l s e v ie r S c ie n c e P u b l i s h e r s B . V . ( B io me d ic a l D iv i s io n )

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1 7 6

h y d r o p h i l i z a t i o n o f t h e h o s t m o l e c u l e w i t h a c o n -c o m i t a n t i m p r o v e m e n t o f it s a p p a r e n t s o l u b il i tya n d d i s s o l u t i o n r a t e ( D u c h S n e e t a l . , 1 9 8 5 a , 1 9 8 7 ) .F u r t h e r m o r e , t h e r e is g e n e ra l ly a n i m p r o v e m e n t i ns t a b i l i t y t o a i r a n d l i g h t ( D u c h ~ n e e t a l . , 1 9 8 5 b ,1987) .T h e p u r p o s e o f t h e w o r k p r e s e n t e d h e r e w a s t op r e p a r e a n i n c l u s i o n o f r e t i n o i c a c i d i n f l - c y c l o -d e x t r i n , d e s p i t e t h e f a c t t h a t t h e h i g h i n s t a b i l i t y t oa i r a n d l i g h t o f r e t i n o i c a c i d i m p e d e s t h e u s e o ft h e g r i n d in g m e t h o d , a n d , d u e t o i ts e x t r e m e l y lo ws o l u b i l it y in m a n y s o l v e n ts , t h is c o n s i d e r a b l y l i m i tst h e p o s s i b i l i t y o f u s i n g a c o p r e c i p i t a t i o n m e t h o d .

M a t e r ia l s a n d M e t h o d sMaterialsR e t i n o i c a c i d , o r 3 , 7 - d i m e t h y l - 9 - ( 2 , 6 , 6 - t r i -m e t h y l - l - c y c l o h e x e n - l - y l ) - 2 , 4 , 6 , 8 - n o n a t e t r a e n o i ca c i d ( S c h e m e 1 ) , w a s p r o v i d e d b y P r o d u i t s R o c h e( P a r i s ~ F r a n c e ) a n d u s e d w i t h o u t a n y p r e l i m i n a r yt r e a t m e n t .

I t s m o l e c u l a r w e i g h t i s 3 0 0 . 4 4 , a n d i t s m e l t i n gp o i n t b e t w e e n 1 8 0 a n d 1 8 2 C . I t a p p e a r s i n t h ef o r m o f t h i n y e l l o w c r y st a l s, i n s o l u b l e i n w a t e r ,s l i g h t l y s o l u b l e i n e t h a n o l a n d c h l o r o f o r m , a n ds o l u b l e i n i s o p r o p a n o l , d i o x a n e , a c e t o n e , e t h e ra n d b o i l i n g b e n z e n e . I t i s u n s t a b l e i n h e a t a n dl i g h t , a n d s o l u t i o n s a r e d e s t a b i l i z e d i n t h e p r e s -e n c e o f o x i d i z i n g a g e n t s .

f l - C y c l o d e x t r i n , o r c y c l o - h e p t a a m y l o s e , w a sp r o v i d e d b y R o q u e t t e F r 6 r e s ( L e s t r em , F r a n c e ) i na p u r i t y o f a t l e a s t 99 % , a n d e m p l o y e d w i t h o u tp a r t i c u l a r p u r i f i c a t i o n .

T h e s o lv e n t s e m p l o y e d w e r e a n a l y t ic a l g r a d e .

Preparation of the inclusionT h e i n c l u s i o n w a s p r e p a r e d b y t h e c o p r e c i p i ta -

H CH CH COOH

CHS c h e m e 1 .

t i o n m e t h o d , u s i n g a n o r g a n o - a q u e o u s s o l u t i o n o fr e t i n o i c a c i d a n d f l - c y c l o d e x t r i n .

T h e s o l v e n t s i n v e s t i g a t e d w e r e w a t e r - m i s c i b l eo r g a n i c s o l v e n t s c a p a b l e o f d i s s o l v i n g t h e r e t i n o i ca c i d a n d g i v i n g a c l e a r so l u t i o n w h e n a d d e d t o a na q u e o u s s o l u t i o n o f c y c l o d e x t r i n . T h e y w e r ea c e t o n e , d i o x a n e a n d i s o p r o p a n o l .

T h e p r o c e d u r e c o n s i s t e d i n m i x i n g a n a q u e o u ss o l u t i o n o f f l - c y c l o d e x t r i n w i t h a n o r g a n i c s o l u -t i o n o f r e t i n o i c a c id , i n o r d e r t o o b t a i n e q u i m o l e c -u l a r a m o u n t s o f t h e t w o p r o d u c t s . T h e c o n c e n t r a -t i o n s o f t h e t w o s o l u t i o n s w e r e c a l c u l a t e d i n o r d e rt o a v o i d t h e e x t e m p o r a n e o u s p r e c i p i t a t i o n o f o n eo r o t h e r o f t h e c o m p o n e n t s a t t h e t im e o f m i x in g .

A c e t o n e d i d n o t l e a d t o a c l e a r s o l u t i o n . D i -o x a n e l e d t o t h e f o r m a t i o n o f a n i n c l u s i o n c o m -p o u n d a f t e r 1 2 h o f s t i r r i n g , b u t u n f o r t u n a t e l yr e t i n o i c a c i d w a s p r o g r e s s i v e l y d e g r a d e d w i t h t h i ss o l v e n t . F o r t h e s e r e a s o n s , t h e t w o s o l v e n t s w e r en o t u s e d s u b s e q u e n t l y .

O n l y i s o p r o p a n o l w a s r e t a in e d . T h e f o r m a t i o no f t h e i n c l u s i o n i s v e r y s l o w . H e n c e , t o a v o i d a n yd e g r a d a t i o n o f r e t i n o i c a c i d , s t i r r i n g m u s t b e c a r -r i e d o u t s h i e l d e d f r o m l i g h t a n d a t l o w t e m p e r a -t u r e ( 6 C ) . T h e s e s p e c i f ic c o n d i t i o n s l e d to t h eu s e o f v e r y d i l u t e s o l u t i o n s , e s p e c i a l l y f o r f l -c y c l o d e x t r i n .

T h e f o l lo w i n g p r o t o c o l w a s e s t a b li s h ed . T w op a r t s o f a n i s o p r o p a n o l i c s o l u t io n o f r e t i n o i c a c id( 4 . 1 0 - 3 M ) w e r e a d d e d , w h i l s t s ti rr in g , t o o n ep a r t o f a n a q u e o u s s o l u t i o n o f f l- c y c l o d e x t r in ( 8 .1 0 - 3 M ) . T h e s o l u t i o n o b t a i n e d w a s t h e n b r o u g h tt o 6 C a n d s t i rr e d .

U n d e r t h e s e c o n d i t i o n s , s p o n t a n e o u s p r e c i p i t a -t i o n o f t h e i n c l u s io n d o e s n o t o c c u r . T h e i n c l u s io nf o r m e d m u s t t h e r e f o r e b e i s o l at e d b y e v a p o r a t i o no f t h e s o lv e n t in a r o t a t o r y v a c u u m e v a p o r a t o r . I no r d e r t o e l i m i n a t e t h e u n s t a b l e a n d i r r i t a t i n g f r e er e t i n o i c a c i d p o s s i b l y p r e s e n t i n t h e c o p r e c i p i t a t e ,i t is r a p i d l y w a s h e d w i t h i s o p r o p a n o l .

T h e p r e s e n c e a n d q u a n t i t a t i v e d e t e r m i n a t i o n o fr e t i n o i c a c i d i n t h e p r o d u c t w e r e e v a l u a t e d b yu l t ra v i o l e t s p e c t r o p h o t o m e t r y ( P e r k i n E l m e r 5 50 ).T h e s o l v e n t u s e d w a s D M S O , w h i c h i s a s o l v e n tf o r b o t h r e t i n o i c a c id a n d f l -c y c l o d e x tr i n . T h em a x i m a l a b s o r p t i o n o f r e t in o i c a c i d i n D M S O is3 6 0 n m ( F ig . 1 ), a n d c y c l o d e x t r i n h a s n o U Va b s o r p t i o n .

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300 350 4~0 4 ~ ~ (nm)Fig. 1. Ma ximum ultraviolet absorption of retinoic ac id inDMSO,

177

A f t e r s t i r r i n g f o r 1 6 d a y s , o n l y 2 0 % o f t h ei n i t i a l r e t i n o i c a c i d i s i n c l u d e d i n t h e f l - c y c l o -d e x t r i n .

Examination of the inclusionT h e m i c r o s c o p i c a s p e c t o f t h e r a w m a t e r i a l si s o l a t e d w a s c o m p a r e d w i t h t h a t o f t h e p r o d u c to b t a i n e d b y c o p r e c i p i t a t i o n / e v a p o r a t i o n b y e x -a m i n a t i o n u n d e r t h e s c a n n i n g e l e c t r o n m i c r o s c o p e( C a m e c a ) .

T h e r e a l i t y o f t h e i n c l u s i o n w a s c o n f i r m e d b ys u b j e c t i n g t h e v a r i o u s p r o d u c t s t o a n a l y s i s b yc i r c u l a r d i c h r o i s m ( J o b i n Y v o n I I I ) , d i f f e r e n t i a ls c a n n i n g c a l o r i m e t r y ( in o p e n c a p s u l e , t o a l l o wt h e e v a p o r a t i o n o f t h e c r y s t a l l iz a t i o n w a t e r o f t h e/ 3 - c y c l o d e x t r in ) ( D u P o n t 9 9 0 ), a n d X - r a y d i f -f r a c t o m e t r y (P h i li p s P W 1 8 40 e q u i p p e d w i t h ac o p p e r a n t i c a t h o d e ) .T h e a q u e o u s s o l u b i l i t y o f r e t i n o i c a c i d i n v a r i -o u s f o r m s w a s d e t e r m i n e d i n d i s ti ll e d w a t e r ( p H5 . 8 4 - 5 .9 0 ) b y d i s p e rs i n g a q u a n t i t y o f p r o d u c tc o r r e s p o n d i n g t o a n e x c e s s a m o u n t o f r e t i n o i ca c i d , o r 5 m g , i n 8 m l o f d is t i ll e d w a t e r , k e p t a t6 C , s h i e l d e d f r o m l i g h t , a n d s t i r r e d f o r 6 8 h . 1m l o f t h e f i l t e r e d s o l u t i o n i s t h e n a d d e d t o 1 rn l o fi s o p r o p a n o l , a n d t h e q u a n t i t y o f r e t i n o i c a c i dd i s s o l v e d i s d e t e r m i n e d b y U V a b s o r p t i o n a t 3 4 4n m ( P e r k i n E l m e r 5 5 0 ). Fig. 2. S canning electron microscopyof/~-cy clode xtrin ~8-CD),retinoic acid (RA), and coprecipitated nclusion (RA/~8-CD).

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178R e s u l t s a n d D i s c u s s i o n

A s p r e v i o u s l y m e n t i o n e d , i s o p r o p a n o l w a s t h eo n l y s o l v e n t w h i c h c o u l d b e u s e d w i t h o u t d e g r a d a -t i o n o f r e t i n o i c a c i d .Microscopic aspect

A n a l y s i s b y t h e s c a n n i n g e l e c t r o n m i c r o s c o p er e v e a l e d t h a t , w h e r e a s f l - c y c l o d e x t r i n c r y s t a ll i z e si n a r e l a t i v e l y l a r g e p o l y h e d r a l f o r m ( F i g . 2 A ) ,r e t i n o i c a c i d a p p e a r s a s n e e d l e s o r e l o n g a t e dc r y s t a l s ( B ) . T h e p r o d u c t o b t a i n e d a f t e r e v a p o r a -t i o n i s a m o r p h o u s ( C ) . T h i s a m o r p h o u s f o r m i sc h a r a c t e r is t i c o f th e p r o d u c t o b t a i n e d h e re , a n d i sn o t t h e c o n s e q u e n c e o f t h e e v a p o r a t i o n p r o c e s s ,b e c a u s e i t h a s b e e n v e r y s l o w d u e t o t h e l o wt e m p e r a t u r e , a n d , i n t h e s e c o n d i t i o n s , i t s h o u l dn o r m a l l y n o t i m p e d e a n y c r y s t a l l i z a t i o n , a s h a sb e e n d e m o n s t r a t e d p r e v i o us l y w i t h a d e r m o c -or t i co id (Glomot e t a l . , 1988) .Reality of the inclusionS i n c e f l - c y c l o d e x t r i n i s a s y m m e t r i c a l m o l e c u l e ,i t d o e s n o t p r e s e n t a n y d i c h r o i c a c t i v i t y . O n t h eo t h e r h a n d , r e t i n o i c a c i d ( F i g . 3 ) d i s s o l v e d i nD M S O h a s a s i g n i f i c a n t d i c h r o i c a c t i v i t y , c h a r -a c t e r i s t i c o f i t s s p a t i a l d i s p o s i t i o n . S i n c e t h e d i -c h r o i c a c t i v it y o f t h e p r o d u c t o b t a i n e d b yc o p r e c i p i t a t i o n i s d i f f e r e n t fr o m t h a t o f p u r e r e ti -n o i c a c i d , t h i s r e v e a l s t h a t a n i n t e r a c t i o n t o o kp l a c e b e t w e e n r e t i n o i c a c i d a n d f l - c y c l o d e x t r i n ,~ I ~ E m o l - I - c m - l ) ~ ' ~ ~ R A

/ t nm )io o ~ ~ o 4~o >

R A / B C D

F ig . 3 . C i r c u la r d i c h r o i s m p a t t e r n s o f f r e e r e t in o ic a c id ( RA)a n d r e t i n o i c ac i d i n c l u d e d i n / ~ - c y c l o d e x t r i n RA/B-CD).

e n d o, ~ - C D

R A I ~ 3 - C D

R A I ~ - C D

t e m p e r a t u r e C )1 200 300

F ig . 4 . D i f f e r e n t i a l s c a n n in g c a lo r ime t r y c u r v e s o f f re e r e t in o ica c id ( RA) , fl-cyclodextrin ( f l -C D ) , u n w a s h e d c o p r e c i p i t a t e ( UR A / ~ - C D ) a n d w a s h e d c o p re c i pi t a te (W RA/fl-CD).

m o d i f y i n g it s s p a ti a l d i s p o s i ti o n a n d c o r r e s p o n d -i n g p r o b a b l y t o a n i n c l u s i o n .T h e d i f f e r e n t i a l s c a n n i n g c a l o r i m e t r y c u r v e s o f

t h e r a w m a t e r i a l s ( r e t i n o i c a c i d a n d f l - c y c l o -d e x t r i n ) c o m p a r e d w i t h t h o s e o b t a i n e d b yc o p r e c i p i t a t i o n b e f o r e a n d a f t e r w a s h i n g ( F i g . 4 )c o n f i r m n o t o n l y a n i n t e r a c t i o n b e t w e e n r e t i n o i ca c i d a n d f l - c y c l o d e x t r i n , b u t a r e a l i n c l u s i o n . I nf a c t, t h e c h a r a c t e r is t i c t h e r m a l a c c i d e n t o f r e t i n o i ca c i d , c o r r e s p o n d i n g t o i t s m e l t i n g p o i n t a t 1 80 o C ,d o e s n o t a p p e a r i n t h e w a s h e d c o p r e c i p i t a te , b u t i sf o u n d a t a h i g h e r t e m p e r a t u r e ( 28 2 C ) b e f o r e t h eb r o w n i n g o f fl - c y c lo d e x t r in , w h i c h o c c u r s b e t w e e n3 0 0 a n d 3 5 0 C . F o r t h e u n w a s h e d c o p r e c i p i ta t e ,t h e f u s i o n p e a k o f t h e f r e e r e t i n o i c a c i d ( a t 1 80 o C )a p p e a r s s i m u l t a n e o u s l y w i t h t h a t o f t h e re t i n o i ca c i d c o p r e c i p i t a t e d w i t h f l - c y c l o d e x t r i n ( a t2 8 2 C ) . T h i s d i s p l a c e m e n t o f t h e f u s i o n p e a k o fr e t in o i c a c i d c o n f i r m s t h a t c o p r e c i p i t a t i o n l e a d s t oan inclusion: r e t i n o i c a c i d i s p r o t e c t e d b y t h ef l -c y c l o d e x t r i n r in g m o l e c u le . I t s h o u l d b e n o t e dt h a t t h e w a t e r m o l e c u l e s o f f l - c y c l o d e x t r in d o n o td i s a p p e a r i n t h e c o p r e c i p i t a t e i n c l u s i o n o b t a i n e d .T h i s c a n b e e x p l a i n e d p a r t l y b y t h e f a c t t h a t t h ec o p r e c i p i t a te h a s b e e n w a s h e d w i t h i s o p r o p a n o l i no r d e r t o e l i m i n a t e t h e f r e e r e t i n o i c a c i d , a n d h a sn o t b e e n w a s h e d w i t h w a t e r t o e l i m i n a t e t h e f r e ec y c l o d e x t r i n w h o s e q u a n t i t y i s u n k n o w n . I n f a c t ,a f t e r t h e U V s p e c t r o p h o t o m e t r i c d e t e r m i n a t i o n ,

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f l - c y c lo d e x t r in ( P M ) , a n d e o p r e c ip i t a t e d in c lu s io n o f r e t in o ica c i d i n / 3 - c y c l o d e x t r i n ( R A / f l - C D ) .

t h e a m o u n t o f re t in o i c a c id i n t h e d r y c o m p o u n di s 2 0 % , w h i c h c o r r e s p o n d s t o 1 m o l e c u l e o f r e t i -n o i c a c i d f o r 4 m o l e c u l e s o f f l - c y c l o d e x t r i n . T h i sd o e s n o t m e a n t h a t t h e r e a r e 3 c y c l o d e x t r i n m o l e -c u l e s i n e x c e s s , b e c a u s e w e d o n o t k n o w i f t h el o n g h y d r o c a r b o n c h a i n o f r e t i n o i c a c i d r e t a i n s ,m o r e o r l e s s , s o m e c y c l o d e x t r i n m o l e c u l e s .

T h e X - r a y d i f f r a c t o m e t r y p a t t e r n ( F ig . 5 ) o f t h ep h y s i c a l m i x t u r e o f r e t i n o i c a c i d a n d f l - c y c l o -d e x t r i n i s a p p r o x i m a t e l y t h e s u p e r p o s i t i o n o f t h ep a t t e r n s o f t h e r a w m a t e r i a l s . O n t h e o t h e r h a n d ,t h e c o p r e c i p i t a te p r o d u c t h a s a c o m p l e t e l y d i f fe r -e n t p a t t e r n i n w h i c h i t i s n o l o n g e r p o s s i b l e t od i s t i n g u i s h t h e c h a r a c t e r i s t i c p e a k s o f r e t in o i c a c i d ,t h u s c o n f i r m i n g t h e e x i s te n c e o f a n e w c o m p o u n d .S o m e p e a k s o f f re e / ~ - c y c l o d e x t r i n a p p e a r a r o u n d1 8 C . F u r t h e r m o r e , t h e a m o r p h o u s c h a r a c t e r o ft h e i n c l u s i o n is o b v i o u s , c o m p a r e d w i t h t h e p h y s i -c a l m i x t u r e .Aqueous solubilityI f f u r th e r p r o o f w e r e n e e d e d , t h e a q u e o u s s o l u -b i l i t y o f r e t i n o i c a c i d f r o m t h e i n c l u s i o n c o m -p o u n d , c o m p a r e d w i t h t h a t f r o m t h e p h y s i c a l m i x -t u r e, c o n f i r m e d t h e r e a l i t y o f th e i n c l u s io n . R a wr e t i n o i c a c i d i s a l m o s t i n s o l u b l e i n w a t e r ( l e s s t h a n0 .5 m g / 1 ) . I t s s o l u b i l it y f r o m t h e p h y s i c a l m i x t u r ei n c re a s e s t o 12 m g / 1 , a n d f r o m t h e i n c l u s io n c o m -p o u n d i t r e a c h e s 1 6 0 m g / 1 .

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T h e f e a s i b il i ty o f p r e p a r i n g a n i n c l u s i o n c o m -p o u n d o f r e t i n o i c a c i d i n / 3 -c y c lo d e x t ri n b y ac o p r e c i p i t a t i o n m e t h o d h a s b e e n d e m o n s t r a t e d .H o w e v e r , d u e t o t h e l o w s o l u b i li t y o f r e t in o i c a c i di n v a r i o u s w a t e r - m i s c i b l e s o l v e n t s , a n d t o i t s g r e a ti n s t a b i l i t y t o a i r a n d l i g h t , t h e p r o c e d u r e i s r a t h e rd i f f ic u l t to b r i n g i n t o o p e r a t i o n . N e v e r th e l e s s , t h en e w c o m p o u n d p r e s e n t i n g a h i g h l y i n c r e a s e d s o lu -b i l i t y s e e m s t o b e o f g r e a t i n t e r e s t f o r d e r m a t o -l o g ic a l a p p l i c a t io n s , a s a l r e a d y p r o v e d b y p r e -l i m i n a r y i n v i v o s t u d i e s .

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s t u d y o f t h e i n d u c t i o n o f e p i d e r m a l h y p e r p l a s ia b y n a t u r a la n d s y n th e t i c r e t in o id s . J. Pharmacol. Exp. Ther. 237( 1 9 8 6 ) 3 1 - 3 5 .

D u c h d n e , D . , D e b r u d r e s , B . a n d V a u t i o n , C ., I m p r o v e m e n t o fd r u g s t a b i l i ty b y c y c lo d e x t r in in c lu s io n c o mp le x a t io n . STPPharma 1 ( 1 9 8 5 a ) 3 7 - 4 3 .D u c h S n e , D . , G l o m o t , F . a n d V a u t i o n , C . , P h a r m a c e u t i c a la p p l i c a t io n s o f e y c lo d e x t r in s . I n D . Du c h S n e ( Ed . ) , Cyclo-dextrins and their Industrial Uses Ed i t io n s d e S a n td , P a r i s ,1987.

D u c h ~ n e , D . , V a u t i o n , C . a n d G l o m o t , F . , A m d l i o r a ti o n d e l ad i s s o lu t io n e t d e l a b io d i s p o n ib i l i t6 d e s p r in c ip e s a c t i f s p a rin c lu s io n d a n s l e s c y c lo d e x t r in e s . STP Pharma 1 ( 1 9 8 5 b )3 2 3 - 3 3 2 .

Glo mo t , F . , Be n k e r r o u r , L . , Du c h S n e , D . a n d P o e lma n , M . C . ,I m p r o v e m e n t i n a v a i l a b i l i t y a n d s t a b i l i t y o f a d e r m o c -o r t i c o id b y in c lu s io n in f l - c y c lo d e x t r in . Int. J. Pharm. 4 6( 1 9 8 8 ) 4 9 - 5 5 .

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a n d d o s e . J. Inoest. Dermatol. 9 1 ( 1 9 8 8 ) 5 6 - 6 1 .Saura t , J .H. , Retinoids New Trends in Research and TherapyKarger , Base l , 1985.Weiss , J .S . , El l is , C.N. , Headington , J .T . , Tincof f , T . , Ham-i l to n , T . A . a n d Vo o r h e e s , J . J . , To p ic a l t r e t in o in imp r o v e s

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