Controlled-Release Technology - American Chemical Society

Chapter 6

Physicochemical Models for Percutaneous Absorption 1

2

J. Hadgraft and Richard H. Guy 1

Welsh School of Pharmacy, UWIST, P.O. Box 13, Cardiff, CF1 3XF, United Kingdom School of Pharmacy, University of California, San Francisco, CA 94143

Downloaded by UNIV OF ALABAMA on March 17, 2016 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch006

2

A mathematical model which predicts the process of percutaneous absorption based on the physicochemical properties of the permeant is described. Its relevance in predicting transdermal drug delivery is assessed using nitroglycerin as an example. The model has the flexibility to allow for drug loss by processes such as volatilisation, microbial degradation, enzyme metabolism. The kinetic steps involved in skin penetration are modified by the presence of penetration enhancers. The model allows a mechanistic interpretation of the potential role of such percutaneous promoters in transdermal drug delivery. The modelling can also be modified to describe dermal absorption in the neonate where it has been used successfully to predict the transdermal delivery of theophylline.

M a t e r i a l s have been a p p l i e d t o t h e s k i n f o r many y e a r s t o o b t a i n medical b e n e f i t . There a r e r e p o r t s t h a t t h e E g y p t i a n s a p p l i e d o i n t m e n t s t o t h e s k i n but i t took u n t i l t h e l a t e n i n e t e e n t h c e n t u r y t o e s t a b l i s h t h a t compounds such as s a l i c y l i c a c i d c o u l d be absorbed p e r c u t a n e o u s l y and t h a t t o x i c e f f e c t s c o u l d be produced from a g e n t s s u p p l i e d t o t h e s k i n s u r f a c e [J_][2]. Throughout t h e f i r s t h a l f o f the t w e n t i e t h c e n t u r y many advances were made w i t h r e g a r d t o an u n d e r s t a n d i n g o f t o p i c a l drug d e l i v e r y f o r l o c a l e f f e c t but i t has o n l y been i n t h e l a s t decade t h a t drug d e l i v e r y t h r o u g h t h e s k i n f o r systemic effect has been seriously considered. In order t o understand t h e advantages and d i s a d v a n t a g e s o f t r a n s d e r m a l drug d e l i v e r y i t i s i m p o r t a n t t o have a thorough comprehension o f t h e p h y s i c o c h e m i c a l parameters which c o n t r o l p e r c u t a n e o u s a b s o r p t i o n . I t i s t h e s e f a c t o r s and how they may be m o d e l l e d which t h i s c h a p t e r addresses.

0097-6156/87/0348-0084$06.00/0 © 1987 American Chemical Society

Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

6.

HADGRAFT AND GUY


Route o f

Percutaneous Absorption

85

penetration

I n d e f i n i n g a model f o r p e r c u t a n e o u s a b s o r p t i o n i t i s n e c e s s a r y to i d e n t i f y the r o u t e by which a drug m o l e c u l e c r o s s e s the s k i n . For a l l but the most l i p o p h i l i c m a t e r i a l s , the p r i n c i p a l b a r r i e r to p e n e t r a t i o n i s the s t r a t u m corneum. There a r e , however, a number o f routes a diffusing drug m o l e c u l e can take in traversing this outermost l a y e r o f the e p i d e r m i s . These a r e d e p i c t e d s c h e m a t i c a l l y i n F i g u r e 1. The l a y e r o f sebum on the s k i n s u r f a c e does not a c t as a barrier and can largely be ignored for assessing percutaneous absorption. Shunt diffusion through the appendages has been s u g g e s t e d as b e i n g s i g n i f i c a n t , p a r t i c u l a r l y d u r i n g the p e r i o d i m m e d i a t e l y a f t e r drug a p p l i c a t i o n . However the s m a l l s u r f a c e a r e a a v a i l a b l e f o r d i f f u s i o n i n d i c a t e s t h a t l a r g e c o n c e n t r a t i o n s o f drug are not transported via this route. The e c c r i n e glands are c e r t a i n l y o f no s i g n i f i c a n c e . There has been l i m i t e d documentation i n which the p i l o s e b a c e o u s system has been i m p l i c a t e d where the formulation contains high concentrations of surfactant [k]. The p r i n c i p a l r o u t e s o f p e n e t r a t i o n are thus t r a n s c e l l u l a r and intercellular. C u r r e n t l y t h e r e i s c o n s i d e r a b l e debate as t o which o f t h e s e p r e d o m i n a t e s . Work w i t h e s t e r s o f n i c o t i n i c a c i d has shown t h a t the i n t e r c e l l u l a r c h a n n e l s a r e s i g n i f i c a n t [5.] and c o n s i d e r a b l e e f f o r t i s b e i n g conducted t o i d e n t i f y t h e i r e x a c t n a t u r e and r o l e . M i c r o s c o p i c e x a m i n a t i o n shows t h a t they c o n t a i n s t r u c t u r e d l i p i d s the c h e m i c a l n a t u r e o f which i s complex [ 6 ] . Cholesterol esters, cerebrosides and sphingomyelins are present i n a s s o c i a t i o n with o t h e r l i p i d s i n s m a l l e r c o n c e n t r a t i o n s . I t i s l i k e l y t h a t the main b a r r i e r to s k i n p e n e t r a t i o n r e s i d e s i n the c h a n n e l s and that a d i f f u s i n g drug m o l e c u l e e x p e r i e n c e s a l i p i d environment which has considerable structure. Penetration enhancers may act by t e m p o r a r i l y a l t e r i n g the n a t u r e o f the s t r u c t u r e d l i p i d s , perhaps by lowering t h e i r normal phase t r a n s i t i o n temperature which occurs around 38°C. When a drug has d i f f u s e d through the s t r a t u m corneum i t must p a r t i t i o n from a p r i m a r i l y l i p i d r i c h environment t o one which i s p r e d o m i n a n t l y aqueous i n n a t u r e , the v i a b l e e p i d e r m i s . It i s p o s s i b l e that t h i s p a r t i t i o n i n g process can c o n t r o l the overall t r a n s f e r o f a drug to the s y s t e m i c c i r c u l a t i o n . C o n s e q u e n t l y any assessment of the physicochemical parameters which influence p e r c u t a n e o u s a b s o r p t i o n must a l s o take i n t o a c c o u n t the p a r t i t i o n i n g c h a r a c t e r i s t i c s o f the d r u g . I t i s also feasible that penetration enhancers may a c t , not o n l y by a f f e c t i n g the s t r u c t u r e d lipid b a r r i e r , but a l s o i n a i d i n g p a r t i t i o n i n g a t the s t r a t u m corneum -viable tissue interface. K i n e t i c d e s c r i p t i o n of percutaneous

absorption

The d i f f e r e n t s t e p s i n v o l v e d i n drug t r a n s f e r from a d e l i v e r y system t o the cutaneous c i r c u l a t i o n a r e shown i n F i g u r e 2 [ 7 - 1 0 ] , Drugs d i f f u s i n g t h r o u g h the s k i n may be s u b j e c t t o v a r i o u s l o s s p r o c e s s e s which a r e d i f f i c u l t to q u a n t i f y but w i l l be d i s c u s s e d . The first s t e p i n the t o t a l t r a n s f e r p r o c e s s i s d i f f u s i o n from the d e v i c e . In i t s s i m p l e s t form, the ' d e v i c e c o u l d be an ointment base which w i l l 1


CONTROLLED-RELEASE TECHNOLOGY

sebum epidermal

append ageal

inter intra cellular

eccrine

follicular


viable epidermis

Figure

1.

Potential

routes

o f drug t r a n s f e r a c r o s s

Location

loss

formulation

evaporation

skin.

processes

microbial transformation

Stratum corneum

binding skin

metabolism

viable epidermis

dermis' k

4

drug removal circulation

F i g u r e 2. Schematic k i n e t i c r e p r e s e n t a t i o n o f drug a c r o s s t h e s k i n and a s s o c i a t e d l o s s p r o c e s s e s .

into

transfer


6.

HADGRAFT AND

87

Percutaneous Absorpnon

GUY

r e l e a s e drug t o the s k i n s u r f a c e w i t h f i r s t o r d e r k i n e t i c s ( k ) . In a membrane moderated t r a n s d e r m a l system t h e r e w i l l be two i n p u t functions describing drug delivery t o the skin. The contact a d h e s i v e which c o n t a i n s a l o a d i n g dose o f the drug w i l l r e l e a s e i t s payload with f i r s t order k i n e t i c s ( k ) , i n a s i m i l a r f a s h i o n to a c o n v e n t i o n a l t o p i c a l dose. The membrane moderation w i l l a l s o ensure t h a t drug i s r e l e a s e d f o r a p r o l o n g e d p e r i o d o f time w i t h z e r o o r d e r kinetics ( k ) . The t o t a l amount a r r i v i n g at the s k i n s u r f a c e w i l l be the sum o f t h e two. A t h i r d t y p e o f d e v i c e r e l e a s e s drug w i t h 'square r o o t o f t i m e k i n e t i c s and c o n s t a n t b l o o d l e v e l s o f the drug a r e r e l i a n t on the s k i n i t s e l f b e i n g the r a t e d e t e r m i n i n g s t e p i n d e l i v e r y t o the s y s t e m i c c i r c u l a t i o n . At the j u n c t i o n between the d e v i c e and the s k i n s u r f a c e t h e drug w i l l e x p e r i e n c e a phase change and hence a p a r t i t i o n i n g s t e p . The d e s i g n o f p o l y m e r i c and a d h e s i v e systems i n t r a n s d e r m a l drug delivery should ensure that this step is thermodynamically f a v o u r a b l e , i . e . the drug p a r t i t i o n s w e l l i n t o the s t r a t u m corneum lipids. Once i n t o the s t r a t u m corneum the drug d i f f u s e s a t a slow rate. T r a n s f e r t h r o u g h the s k i n i s s l o w e s t i n t h i s r e g i o n and a f i r s t o r d e r c o n s t a n t , k-|, can be w r i t t e n t o d e s c r i b e t h i s i n terms o f the d i f f u s i o n c o e f f i c i e n t o f the drug D and the d i f f u s i o n a l path length l . a

a

0


1

s c

s

k

1

c

2

= Dsc/l sc

(1)

D i f f u s i o n then continues through the v i a b l e t i s s u e at a f a s t e r r a t e and a second r a t e c o n s t a n t , k2, can be w r i t t e n i n a s i m i l a r manner

k

2

= D

v e

/l2

y e

(2)

where the s u b s c r i p t s now r e f e r t o the v i a b l e e p i d e r m i s . In p r e v i o u s work i t has been shown t h a t t h e s e r a t e c o n s t a n t s a r e r e l a t e d t o the m o l e c u l a r s i z e and hence m o l e c u l a r weight (M) o f the d i f f u s a n t [ 1 1 ] . The r a t e c o n s t a n t s can be p r e d i c t e d based on p r e v i o u s d a t a f o r b e n z o i c a c i d and f o r s u b s t a n c e s w i t h m o l e c u l a r weights o f l e s s than 500 Da,

1

k^n" ) =

0.91M-1/3

(3)

k ( h - ) = 14.36M-1/3

(4)

1

2

From F i g u r e 2, i t i s a p p a r e n t t h a t t h e r e i s a l s o a p a r t i t i o n i n g s t e p as the drug d i f f u s e s from the s t r a t u m corneum t o the v i a b l e t i s s u e , t h i s can be d e s c r i b e d by a backward r a t e c o n s t a n t , kg. Empirically it has been shown t h a t the r a t i o kg/k2 can be r e l a t e d t o the o c t a n o l - w a t e r (pH 7.4) p a r t i t i o n c o e f f i c i e n t o f t h e drug d i v i d e d by



88


5 [ 1 1 ] . Thus drugs which a r e v e r y l i p o p h i l i c may be h e l d back i n the s t r a t u m corneum. T r a n s f e r a c r o s s both l a y e r s o f s k i n w i l l be f a c i l i t a t e d f o r drugs which have b a l a n c e d p a r t i t i o n i n g b e h a v i o u r and r e a s o n a b l e s o l u b i l i t y i n both o i l and water phases. When t h e drug arrives a t t h e cutaneous vasculature i t e q u i l i b r a t e s r a p i d l y i n t o the systemic c i r c u l a t i o n which has a volume o f d i s t r i b u t i o n , V. E l i m i n a t i o n from t h i s compartment i s d e s c r i b e d by a n o t h e r f i r s t o r d e r r a t e c o n s t a n t ki| ( a l t h o u g h t h i s c o u l d be made more complex) which i s t h e c l a s s i c pharmacokinetic rate of elimination. Using t h e above rate constants i t i s p o s s i b l e to write e q u a t i o n s d e s c r i b i n g t h e plasma c o n c e n t r a t i o n ( C p ) , time ( t ) c o u r s e of a t r a n s d e r m a l l y a p p l i e d drug [9.][V2][J_3]. A simple a n a l y t i c s o l u t i o n i s p o s s i b l e i n t h e case o f t h e z e r o and f i r s t o r d e r r e l e a s e which i s : -

C

f(k )

= Mk k k

a

a

= f (k ) + f (k )

p

1

a

(

2

(5)

0

exp(-qt)

exp(-pt)

\(β-α)(α-ω)( •ω) (α-μ)

f(k )

ω

exp(-q)t )

exp(-||t)

(α-ω) (ω-β)(ω-μ)

(οτμ) (μ-β) ( μ - ω ^

( _ 1 _

= Akok^

0

(α-β)(β- )(β-μ)

-

(6)

expiât)

\ αβε

"

exp(-Rt)

exp(-

(

(7)

Where Μ i s t h e amount o f drug of t h e d e v i c e , k

k

=

ωμ

= a 1î

(ω+μ)

αβ

= k k4;

ε

= k-i+k

2

k

a

+ k

r

i n the adhesive,

+ k

A i s the surface area

1

(α+β) = k + k + k 4 2

3

r


6.


The

HADGRAFT A N D G U Y

loss

89


processes

F i g u r e 2 a l s o shows t h a t v a r i o u s l o s s p r o c e s s e s a r e a l s o p o s s i b l e . From the s u r f a c e o f the s k i n t h e r e a r e two p o t e n t i a l methods by which a drug can be l o s t . I f i t i s not c o v e r e d , i t may d i s a p p e a r as a r e s u l t o f s u r f a c e a b r a s i o n , on t o , f o r example c l o t h i n g . Volatile m a t e r i a l s may e v a p o r a t e and t h i s p r o c e s s i s not e a s i l y q u a n t i f i e d . I t i s apparent t h a t e i t h e r z e r o o r d e r , f i r s t o r d e r o r a c o m b i n a t i o n o f both may o c c u r i n the v o l a t i l i s a t i o n o f an a c t i v e i n g r e d i e n t . The r a t e s have not been q u a n t i f i e d i n many i n s t a n c e s and w i l l be s u b j e c t t o a l a r g e number o f v a r i a b l e s . A l t h o u g h e q u a t i o n s can be d e r i v e d to p r e d i c t the s i g n i f i c a n c e o f t h e s e l o s s p r o c e s s e s t h e y a r e d i f f i c u l t t o j u s t i f y i n l i g h t o f the c u r r e n t p a u c i t y o f e x p e r i m e n t a l data [ J I 4 ] Q 5 ] . A f u r t h e r p o t e n t i a l l o s s p r o c e s s i n v o l v e s metabolism o f the drug by m i c r o - o r g a n i s m s on the s k i n s u r f a c e . H e a l t h y s k i n s u p p o r t s a wide range o f micro organisms, the most common commensal b e i n g Staphylococcus epidermidis. This organism is capable of m e t a b o l i s i n g drugs such as s t e r o i d e s t e r s [±6] and nitroglycerin (GTN) [J7.]. Thus drugs i n t e n d e d f o r both l o c a l and s y s t e m i c e f f e c t may be d e a c t i v a t e d b e f o r e they even p a r t i t i o n i n t o t h e o u t e r l a y e r s o f the s k i n . T h i s e f f e c t can be q u a n t i f i e d and t h e o r e t i c a l r e s u l t s indicate that blood levels of topically applied GTN can be s i g n i f i c a n t l y reduced [ 1 8 ] . W i t h i n the s t r a t u m corneum drug l o s s can o c c u r by b i n d i n g to components o f the s k i n . L i t t l e work has a s s e s s e d t h e magnitude o f such e f f e c t s but some i n v e s t i g a t i o n s have a t t r i b u t e d the f o r m a t i o n o f s t e r o i d r e s e r v o i r s t o b i n d i n g phenomena. B i n d i n g may o c c u r as a r e s u l t o f van der Waals i n t e r a c t i o n s or hydrogen bonding. Another i m p o r t a n t l o s s p r o c e s s i s t h a t o f metabolism by enzymes w i t h i n the s k i n . Many non s p e c i f i c enzymes have been shown to be present i n the skin. These i n c l u d e esterases, oxidases and r e d u c t a s e s [J_9][20]. Thus t h e r e a r e a number o f p o t e n t i a l p r o c e s s e s which may d e a c t i v a t e the drug as i t d i f f u s e s . T h i s d e a c t i v a t i o n can be q u a n t i f i e d but a g a i n t h e r e i s l a c k o f s p e c i f i c d a t a [21 ] [ 2 2 ] , F u r t h e r work i s r e q u i r e d t o monitor the l o c a t i o n and c o n c e n t r a t i o n o f the enzymes p r e s e n t and t o p r o v i d e g u i d e l i n e s about the e x a c t k i n e t i c s o f the m e t a b o l i c p r o c e s s e s . T h i s s t e p i s not n e c e s s a r i l y disadvantageous s i n c e f o r some drugs i t i s p o s s i b l e t o s y n t h e s i s e prodrugs. These p o s s e s s the c o r r e c t p h y s i c o c h e m i c a l p r o p e r t i e s t o o p t i m i s e s k i n p e n e t r a t i o n and d u r i n g the d i f f u s i o n p r o c e s s they a r e m e t a b o l i c a l l y c l e a v e d t o produce t h e a c t i v e drug a t the s i t e a t which i t i s r e q u i r e d [24-26]. Transdermal

d e l i v e r y of

nitroglycerin

S i n c e n i t r o g l y c e r i n has been one o f the most w i d e l y s t u d i e d drugs which have been d e l i v e r e d by the t r a n s d e r m a l r o u t e , the u t i l i t y o f the model w i l l be i l l u s t r a t e d f o r t h i s compound. One membrane moderated d e v i c e r e l e a s e s drug w i t h w e l l d e f i n e d c h a r a c t e r i s t i c s t h a t have been measured i n v i t r o [ 2 7 ] . There i s an i n i t i a l first o r d e r r e l e a s e o f GTN (2mg) from the a d h e s i v e w i t h an e s t i m a t e d rate c o n s t a n t o f 1.3 h " over a s u r f a c e a r e a 10 cm . The z e r o o r d e r r e l e a s e from t h i s d e v i c e has been determined as 36yg/cm /h. The 1

2

2


90


d e s i g n o f t h i s system i s such t h a t GTN p a r t i t i o n s f a v o u r a b l y from the a d h e s i v e i n t o the s t r a t u m corneum. Consequently a s m a l l value of k has been chosen ( l O ' ^ h ) such t h a t p a r t i t i o n i n g does not i n f l u e n c e the r e l e a s e c h a r a c t e r i s t i c s o f t h e d e v i c e . E s t i m a t e s o f k-|. k2 and k3 have been a s s e s s e d from the p h y s i c o c h e m i c a l p r o p e r t i e s o f GTN u s i n g e q u a t i o n s (3) and ( 4 ) . They a r e , r e s p e c t i v e l y , 0.15, 2.36 and 53 h " . The r a t e o f e l i m i n a t i o n o f GTN from the s y s t e m i c circulation, i s 18.2h" w i t h a volume o f d i s t r i b u t i o n o f 231 1 [ 12]. U s i n g these parameters and e q u a t i o n s (6) and (7) g i v e s the theoretical profile shown i n F i g u r e 3. This i l l u s t r a t e s the r e l a t i v e importance o f the f i r s t and z e r o o r d e r p r o c e s s e s . Also i n c l u d e d on t h e graph a r e e x p e r i m e n t a l d a t a showing plasma l e v e l s o f GTN f o l l o w i n g transdermal drug delivery [28]. There i s good agreement between the t h e o r e t i c a l c a l c u l a t i o n s and t h e e x p e r i m e n t a l data. In o t h e r membrane moderated systems f o r the d e l i v e r y o f c l o n i d i n e [JJJ and e s t r a d i o l [ 2 9 ] , e q u a l l y good agreement can be obtained by e s t i m a t i n g plasma levels from the physicochemical p r o p e r t i e s o f the drug and the r e l e v a n t e q u a t i o n s g i v e n above. - 1

r

1


1

Other transdermal systems g i v e r a t e s o f r e l e a s e which are p r o p o r t i o n a l t o the square r o o t o f t i m e . In o r d e r t o model t h i s behaviour i t i s p o s s i b l e to w r i t e a s e r i e s of l i n e a r d i f f e r e n t i a l e q u a t i o n s t o d e s c r i b e t r a n s f e r from the d e v i c e and a c r o s s the s k i n . However u n l i k e the c a s e s o f f i r s t and z e r o o r d e r i n p u t , t / i n p u t does not produce a s i m p l e a n a l y t i c a l s o l u t i o n o f the type g i v e n i n e q u a t i o n ( 5 ) . Plasma l e v e l s have t h e r e f o r e been c a l c u l a t e d u s i n g a numerical approach and by solving the equations using the Runge-Kutta method. F o r GTN d e l i v e r y , i d e n t i c a l r a t e c o n s t a n t s t o t h o s e d e s c r i b e d above have been used f o r k-j, k2, k3 and kjj w i t h an i n p u t c o n s t a n t o f 500 y g / c m / h ° * 5 over a s u r f a c e a r e a o f 8 cm . The drug r e s e r v o i r c o n t a i n s 16 mg o f GTN. The p r e d i c t e d p r o f i l e i s reproduced i n F i g u r e 4. The plasma l e v e l s a r e not as c o n s t a n t as i n the z e r o o r d e r case but t h e r e i s s t i l l r e a s o n a b l e agreement between the t h e o r e t i c a l p r o f i l e and p u b l i s h e d d a t a [30]» T h i s k i n e t i c a p p r o a c h t o d e s c r i b e t r a n s d e r m a l drug d e l i v e r y f o r a range o f i n p u t f u n c t i o n s can be u s e f u l l y employed and, i n view o f the good c o r r e l a t i o n s w i t h i n v i v o d a t a , can be used p r e d i c t i v e l y . 1

2

Physicochemical requirements

2

2

f o r transdermal

delivery

The s t r a t u m corneum forms an e x c e l l e n t b a r r i e r t o p e n e t r a t i o n and thus t r a n s d e r m a l d e l i v e r y i s o n l y f e a s i b l e f o r drugs where the t o t a l d a i l y dose i s l e s s t h a n one o r two m i l l i g r a m s . T h i s c o r r e s p o n d s t o plasma c o n c e n t r a t i o n s o f the o r d e r o f nanograms per milliliter. There i s t h u s a r e s t r i c t i o n t h a t t h e drug must be v e r y p o t e n t . U s i n g the above model i t i s p o s s i b l e t o i d e n t i f y f u r t h e r c o n s t r a i n t s which a r e based on the p h y s i c o c h e m i c a l p r o p e r t i e s o f t h e d r u g . F i r s t l y the drug must p a r t i t i o n i n t o the l i p i d s o f the s t r a t u m corneum. Thus i o n i c compounds w i l l not be s u c c e s s f u l u n l e s s t h e y can be f o r m u l a t e d as i o n p a i r s . I t i s important, t h e r e f o r e , to c o n s i d e r o n l y drugs o r t h e i r complexes which have a p p r o p r i a t e physicochemical properties for partitioning from the topical formulation into the skin lipids. Assuming this process is favourable are there any further constraints? These can be i d e n t i f i e d by c o n s i d e r i n g two drugs which a r e p o t e n t i a l c a n d i d a t e s


HADGRAFT AND GUY


plasma cone (ng/ml) 0.2


0.1

.01

24

12 time

(hours)

F i g u r e 3 · P r e d i c t i o n o f GTN plasma c o n c e n t r a t i o n f o l l o w i n g t r a n s d e r m a l d e l i v e r y from a membrane moderated system. Curve F r e p r e s e n t s t h e c o n t r i b u t i o n from the l o a d i n g dose i n t h e a d h e s i v e , c u r v e Z, t h e z e r o o r d e r d e l i v e r y and c u r v e Τ t h e sum o f t h e two. C o r r e s p o n d i n g i n v i v o d a t a were o b t a i n e d ( s o l i d c i r c l e s ) from r e f . [28]. plasma cone, (ng/ml) 0.4

0.2

time

(hours)

F i g u r e 4. P r e d i c t i o n o f GTN plasma c o n c e n t r a t i o n f o l l o w i n g t r a n s d e r m a l d e l i v e r y from a system which r e l e a s e s w i t h t / k i n e t i c s . C o r r e s p o n d i n g i n v i v o d a t a were o b t a i n e d ( s o l i d c i r c l e s ) from r e f . [28]. 1


2

92


f o r transdermal d e l i v e r y , p r o p r a n o l o l and c h l o r d i a z e p o x i d e . The r e l e v a n t k i n e t i c parameters [J_0] f o r these a r e g i v e n i n T a b l e 1 ·

Kinetic and chlordiazepoxide

Table 1 parameters

biological

propranolol m o l e c u l a r weight log octanol-water partition coefficient t a r g e t plasma cone,(ng/ml) k (ug cm~ h- ) k (h-1) k (h-1) k! (h-1) k (h-1) k (h-1) k (h-1) V (1) A (cm ) M (mg) 2

1


Q

a

r

2

3

4

2

for

propranolol

and

chlordiazepoxide

259

300

1.17 20 35

2.5 700 30

1

1

3

· .

3

· .

ίο- * 0.136 2.15 136 0.07 21 50 100

ίο- * 0.143 2.26 6.67 0.18

2

2

273 30 30

F i g u r e s (5) and (6) show r e s p e c t i v e l y t h e p r e d i c t e d p r o f i l e s f o r p r o p r a n o l o l and c h l o r d i a z e p o x i d e . I t i s immediately apparent t h a t p r o p r a n o l o l i s a drug c a n d i d a t e which c o u l d be c o n s i d e r e d f o r d e l i v e r y using t h i s route of administration. The d e l i v e r y o f chlordiazepoxide i s , however, u n l i k e l y t o s u c c e e d . The p r i m a r y r e a s o n f o r t h i s i s t h e l a r g e v a l u e o f k such t h a t drug t r a n s f e r o u t of the stratum corneum i s slow. Thus drugs which a r e v e r y l i p o p h i l i c i n n a t u r e can p a r t i t i o n w e l l i n t o the s t r a t u m corneum but t r a n s f e r out o f t h i s r e g i o n impedes t h e a r r i v a l o f t h e drug a t t h e cutaneous v a s c u l a t u r e . The o n l y method of circumventing this problem i s by t h e use o f a p e n e t r a t i o n enhancer which w i l l m o d i f y the partitioning characteristics a t t h e stratum corneum-viable epidermis i n t e r f a c e . 3

Penetration

enhancers

In o r d e r t o i n c r e a s e the number o f drugs which can be a d m i n i s t e r e d t r a n s d e r m a l l y , t h e b a r r i e r f u n c t i o n o f t h e s k i n must be r e d u c e d . The k i n e t i c model can be used t o a s s e s s t h e r o l e o f a p e n e t r a t i o n enhancer as a f u n c t i o n o f t h e p h y s i c o c h e m i c a l properties o f the drug. In i t s s i m p l e s t form a p e n e t r a t i o n enhancer may be c o n s i d e r e d t o a c t i n one o f two ways. F i r s t l y i t may i n c r e a s e t h e p e r m e a b i l i t y of the s k i n and, s e c o n d l y , i t may additionally modify t h e p a r t i t i o n i n g c h a r a c t e r i s t i c s a t the stratum corneum-viable t i s s u e interface. F o r i l l u s t r a t i o n , two enhancers have been a r b i t r a r i l y chosen, t h e f i r s t PE1 i n c r e a s e s t h e p e r m e a b i l i t y by a f a c t o r o f 10, i . e . k

Controlled-Release Technology - American Chemical Society

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