Controlled-Release Technology - ACS Publications - American

Chapter 1

Overview of Controlled-Release Drug Delivery Ping I. Lee and William R. Good

Downloaded by UNIV OF WISCONSIN MILWAUKEE on June 15, 2014 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch001

Ciba-Geigy Corporation, Ardsley, NY 10502

During the past two decades, significant advances have been made in the area of controlled release as evidenced by an increasing number of patents, publications, as well as commercial controlled-release products for the delivery of a variety of bioactive agents ranging from pharmaceutical to agricultural and veterinary compounds. This proliferation of interest is a reflection of the growing awareness that by achieving predictable and reproducible release rates of bioactive agents, particularly pharmaceuticals, to the target environment for a desired duration, optimum biological responses, prolonged efficacy, decreased toxicity as well as reduction of required dose level as compared to the conventional mode of delivery can be effectively achieved. So far, the controlled-release pharmaceutical area has gained the most significant growth as a result of intense interdisciplinary efforts involving contributions from chemistry, material science, engineering, pharmacology and other related biological sciences. By improving the way in which drugs are delivered to the target organ, a controlled-release drug delivery system is capable of achieving the following benefits: (1) maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuation; (2) predictable and reproducible release rates for extended duration; (3) enhancement of activity duration for short half-life drugs; (4) elimination of side effects, frequent dosing, and waste of drug; and (5) optimized therapy and better patient compliance. A number of controlled-release drug delivery systems have been developed and some are already commercialized. These include, for example, transdermal nitroglycerin delivery systems for the prevention of angina and oral osmotic pump devices for the delivery of a variety of therapeutic agents. The purpose of this overview chapter is to provide perspectives in the current status and future prospects of controlled release drug delivery. This is accomplished by examining various delivery systems from a mechanistic point of view, exploring applications of these systems, and discussing relevant biopharmaceutical parameters. A major section of this book is devoted to fundamental issues and applications of transdermal and transmucosal delivery systems (Chapter 6,8,17-23). Other developing systems of future potential

0097-6156/87/0348-0001$06.00/0 © 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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a r e a d d r e s s e d by v a r i o u s C h a p t e r s o f t h i s book i n v o l v i n g s e l f - r e g u l a t i n g i n s u l i n d e l i v e r y systems (Chapter 13), h y d r o g e l s (Chapters 5,10-12), drug-polymer c o n j u g a t e s (Chapter 14), and b i o d e g r a d a b l e m i c r o s p h e r e s ( C h a p t e r s 15,16). To p r o v i d e a b r o a d e r scope on the p h y s i c o c h e m i c a l b a s i s o f c o n t r o l l e d r e l e a s e , the fundamental a s p e c t s of d i f f u s i o n i n polymers ( C h a p t e r s 2-4), polymer and d e l i v e r y system c h a r a c t e r i z a t i o n ( C h a p t e r s 7,9) as w e l l as o t h e r r e l a t e d a p p l i c a t i o n s o f d e l i v e r y systems ( C h a p t e r s 24,25) a r e a l s o d i s c u s s e d . C l a s s i f i c a t i o n o f C o n t r o l l e d - R e l e a s e Drug D e l i v e r y Systems. An i d e a l drug d e l i v e r y system i s one which p r o v i d e s the drug o n l y when and where i t i s needed, and i n the minimum dose l e v e l r e q u i r e d t o e l i c i t the d e s i r e d t h e r a p e u t i c e f f e c t s . In p r a c t i c e , such a system s h o u l d p r o v i d e a programmmable c o n c e n t r a t i o n - t i m e p r o f i l e t h a t p r o d u c e s optimum t h e r a p e u t i c r e s p o n s e s . T h i s g o a l can o n l y be a c h i e v e d t o a l i m i t e d e x t e n t w i t h c o n v e n t i o n a l dosage forms. Recent development i n p o l y m e r i c d e l i v e r y systems f o r the c o n t r o l l e d r e l e a s e o f t h e r a p e u t i c a g e n t s has demonstrated t h a t t h e s e systems not o n l y can improve drug s t a b i l i t y b o t h i n v i t r o and i n v i v o by p r o t e c t i n g l a b i l e drugs from h a r m f u l c o n d i t i o n s i n the body, but a l s o can i n c r e a s e r e s i d e n c e time a t the a p p l i c a t i o n s i t e and enhance the a c t i v i t y d u r a t i o n o f s h o r t h a l f - l i f e d r u g s . Therefore, compounds which o t h e r w i s e would have to be d i s c a r d e d due to s t a b i l i t y and b i o a v a i l a b i l i t y problems may be r e n d e r e d u s e f u l through a p r o p e r c h o i c e o f p o l y m e r i c d e l i v e r y system. A u s e f u l c l a s s i f i c a t i o n o f c o n t r o l l e d - r e l e a s e p o l y m e r i c system based on the mechanism c o n t r o l l i n g the drug r e l e a s e i s as f o l l o w s : A. C h e m i c a l l y - c o n t r o l l e d systems a. B i o e r o d i b l e systems b. Drug-polymer c o n j u g a t e s B. D i f f u s i o n - c o n t r o l l e d systems a. M e m b r a n e - r e s e r v o i r systems - Solution-diffusion - Osmotic pumping b. M a t r i x systems - Matrix d i f f u s i o n - Polymer e r o s i o n - Polymer s w e l l i n g - Geometry - Concentration d i s t r i b u t i o n Most o f the d e l i v e r y systems d e s c r i b e d i n t h i s book can be d e s c r i b e d by one o f the above c l a s s i f i c a t i o n s . Chemically-Controlled

Systems

B i o e r o d i b l e Systems. In t h i s system, the polymer m a t r i x c o n t a i n s h y d r o l y t i c a l l y o r e n z y m a t i c a l l y l a b i l e bonds and u n i f o r m l y d i s s o l v e d or d i s p e r s e d drug. As the polymer erodes by h y d r o l y s i s o r enzymatic c l e a v a g e , the drug i s r e l e a s e d t o the s u r r o u n d i n g environment. One major advantage o f such an approach i s the e l i m i n a t i o n o f the need to s u r g i c a l l y remove the d e v i c e a f t e r a p p l i c a t i o n . However, dependi n g on the s p e c i f i c polymer u s e d , the e r o s i o n / d e g r a d a t i o n p r o d u c t s may have d i f f e r e n t degree o f t o x i c i t y . As a r e s u l t o f r e s e a r c h on improved a b s o r b a b l e s u t u r e s , p o l y ( l a c t i c a c i d ) , p o l y ( g l y c o l i c



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Overview of Controlled-Release Drug Delivery

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a c i d ) , and l a c t i c / g l y c o l i c a c i d c o p o l y m e r s , which h y d r o l y z e t o n a t u r a l m e t a b o l i t e s , have been d e v e l o p e d f o r drug d e l i v e r y p u r p o s e s (1_) . O f t e n the terms " b i o e r o d i b l e " and " b i o d e g r a d a b l e " a r e used i n terchangeable. However, " b i o e r o d i b l e " i s u s u a l l y r e s e r v e d f o r s y s tems where the polymer e r o s i o n o c c u r s i n a time s c a l e s i m i l a r t o t h a t o f the drug r e l e a s e . In o t h e r words, the e r o s i o n p r o c e s s has a d i r e c t e f f e c t on the drug r e l e a s e . On the o t h e r hand, " b i o d e g r a d a b l e " polymer i s f o r systems where the polymer d e g r a d a t i o n o c c u r s a f t e r the drug r e l e a s e i s l o n g completed. In t h i s c a s e , the d e g r a d a t i o n p r o c e s s has no d i r e c t e f f e c t on the drug r e l e a s e . As p o i n t e d out by H e l l e r ( 2 ) , polymer e r o s i o n can be c o n t r o l l e d by the f o l l o w i n g t h r e e t y p e s o f mechanisms: (1) w a t e r - s o l u b l e p o l y mers i n s o l u b i l i z e d by h y d r o l y t i c a l l y u n s t a b l e c r o s s - l i n k s ; (2) w a t e r - i n s o l u b l e polymers s o l u b i l i z e d by h y d r o l y s i s , i o n i z a t i o n , o r p r o t o n a t i o n o f pendant groups; (3) h y d r o p h o b i c polymers s o l u b i l i z e d by backbone c l e a v a g e t o s m a l l water s o l u b l e m o l e c u l e s . These mechanisms r e p r e s e n t extreme c a s e s ; the a c t u a l e r o s i o n may o c c u r by a c o m b i n a t i o n o f mechanisms. In a d d i t i o n t o p o l y ( l a c t i c a c i d ) , p o l y ( g l y c o l i c a c i d ) , and l a c t i c / g l y c o l i c a c i d c o p o l y m e r s , o t h e r commonly used b i o e r o d i b l e / b i o d e g r a d a b l e polymers i n c l u d e p o l y o r t h o e s t e r s , p o l y c a p r o l a c t o n e , p o l y a m i n o a c i d s , p o l y a n h y d r i d e s , and h a l f e s t e r s of m e t h y l v i n y l e t h e r - m a l e i c a n h y d r i d e copolymers C3). With r e s p e c t t o the mechanism o f drug r e l e a s e , i t i s i m p o r t a n t to d i s t i n g u i s h between two t y p e s o f h y d r o l y t i c e r o s i o n o f w a t e r - i n s o l u b l e polymers. On one hand, homogeneous e r o s i o n o c c u r s by h a v i n g h y d r o l y s i s a t a u n i f o r m r a t e throughout the m a t r i x . T h i s i s o f t e n r e f e r r e d t o as b u l k e r o s i o n which i s c a p a b l e o f i n c r e a s i n g the drug p e r m e a b i l i t y t h r o u g h the polymer as time p r o c e e d s and t h e r e b y p r o d u c i n g an a c c e l e r a t e d r e l e a s e v i a a c o m b i n a t i o n o f d i f f u s i o n and erosion. On the o t h e r hand, heterogeneous e r o s i o n c o n f i n e s the hyd r o l y s i s to the s u r f a c e o f the d e v i c e and t h e r e f o r e commonly r e f e r r e d to as s u r f a c e e r o s i o n . This process i s capable of g i v i n g r i s e t o a z e r o - o r d e r drug r e l e a s e f o r d e v i c e s w i t h c o n s t a n t s u r f a c e a r e a . M a t h e m a t i c a l a n a l y s i s o f s u r f a c e b i o e r o d i b l e systems has been p r e s e n t e d by Lee (4)who r e c e n t l y a l s o i n v e s t i g a t e d the e f f e c t o f n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n on the k i n e t i c s o f drug r e l e a s e from polymer m a t r i c e s o f v a r i o u s g e o m e t r i e s ( 5 ) . Drug-Polymer C o n j u g a t e s . T h i s system i n v o l v e s drug m o l e c u l e s c h e m i c a l l y bounded to a polymer backbone. The drug w i l l be r e l e a s e d t h r o u g h h y d r o l y t i c or enzymatic c l e a v a g e . Such p o l y m e r i c drug c a r r i e r s a r e a l s o r e f e r r e d to as p o l y m e r i c p r o d r u g s . The attachment of drugs to m a c r o m o l e c u l a r c a r r i e r s a l t e r s t h e i r r a t e o f e x c r e t i o n from the body and p r o v i d e s the p o s s i b l i t y f o r c o n t r o l l e d r e l e a s e over a prolonged p e r i o d . F u r t h e r m o r e , i t l i m i t s the uptake o f drug by c e l l s to the p r o c e s s o f e n d o c y t o s i s , thus p r o v i d i n g the o p p o r t u n i t y t o t a r g e t the drug t o the p a r t i c u l a r c e l l - t y p e where i t s a c t i v i t y i s needed ( 6 ) . Both n a t u r a l polymers such as p o l y s a c c h a r i d e s and s y n t h e t i c polymers such as p o l y l y s i n e , p o l y g l u t a m i c a c i d , p o l y p h o s p h a z e n e s , copolymers o f v i n y l p y r r o l i d o n e , copolymers o f 2-hydroxypropylmetha c r y l a m i d e , and e t c . have been used as drug c a r r i e r s . The s t r u c t u r e o f t h e s e polymers can be m o d i f i e d by the i n c o r p o r a t i o n o f h y d r o p h o b i c u n i t s , sugar r e s i d u e s , o r s u l f o n y l groups t o a c h i e v e a s p e c i f i c tissue a f f i n i t y .



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The drug-polymer l i n k a g e may be c o v a l e n t , i o n i c , o r through some weaker s e c o n d a r y m o l e c u l a r f o r c e s . The polymer backbone may be e i t h e r biodegradable or non-biodegradable. The drug can be p a r t o f the p o l y m e r i c backbone o r a t t a c h e d t o the s i d e - c h a i n e i t h e r d i r e c t l y or t h r o u g h a s p a c e r group. The s p a c e r group i s g e n e r a l l y s e l e c t e d i n such a way t h a t i t may be h y d r o l y z e d o r degraded e n z y m a t i c a l l y under s p e c i f i c e n v i r o n m e n t a l c o n d i t i o n s . Examples o f such d r u g polymer c o n j u g a t e s i n c l u d e the attachment o f a m p i c i l l i n , 6-aminop e n i c i l l a n i c a c i d , daunomycin, and puromycin to N - ( 2 - h y d r o x y p r o p y l ) m e t h a c r y l a m i d e copolymers (]_>§), m e t h o t r e x a t e to p o l y ( L - l y s i n e ) ( 9 ) , and n o r e t h i n d r o n e t o p o l y ( h y d r o x y a l k y l ) - L - g l u t a m i n e ( 1 0 ) . In a d d i t i o n t o d i f f u s i o n r a t e l i m i t a t i o n s as d e s c r i b e d i n the next s e c t i o n , the drug r e l e a s e r a t e i s p r i m a r i l y governed by the r a t e o f c l e a v a g e o f the drug from the polymer. Diffusion-Controlled

System

Membrane-Reservoir Systems. D i f f u s i o n c o n t r o l l e d p o l y m e r i c d e l i v e r y systems a r e f i n d i n g i n c r e a s i n g a p p l i c a t i o n s i n the a r e a o f c o n t r o l l e d r e l e a s e p h a r m a c e u t i c a l s . To a c h i e v e optimum t h e r a p e u t i c e f f e c t s e s p e c i a l l y f o r drugs w i t h s h o r t b i o l o g i c a l h a l f - l i v e s , i t i s o f t e n d e s i r a b l e t o have a z e r o - o r d e r drug r e l e a s e . Membrane-reservoir d e v i c e s , where the drug c o r e i s s u r r o u n d e d by a r a t e - c o n t r o l l i n g membrane, a r e o f t e n employed f o r t h i s p u r p o s e . The p r e s e n c e o f a s a t u r a t e d r e s e r v o i r i n t h i s case i s e s s e n t i a l to m a i n t a i n a constant r a t e o f drug r e l e a s e . The k i n e t i c s o f drug r e l e a s e from such membrane-reservoir systems g e n e r a l l y f o l l o w s e i t h e r a s o l u t i o n - d i f f u s i o n mechanism o r an o s m o t i c pumping mechanism. In the s o l u t i o n - d i f f u s i o n mechanism, the drug t r a n s p o r t o c c u r s by f i r s t d i s s o l v i n g i n the membrane a t one i n t e r f a c e f o l l o w e d by d i f f u s i o n down a c h e m i c a l p o t e n t i a l g r a d i e n t a c r o s s the membrane and e v e n t u a l l y r e l e a s e d from the second i n t e r f a c e i n t o the e x t e r n a l medium. Such s o l u t i o n - d i f f u s i o n mechanism i s t y p i c a l l y o b s e r v e d i n non-porous membranes. A s i m i l a r mechanism i s a l s o r e s p o n s i b l e f o r drug p e r m e a t i o n t h r o u g h s w o l l e n h y d r o g e l membranes as w e l l as porous membranes. In the l a t t e r case the drug p e r m e a t i o n t a k e s p l a c e by d i f f u s i o n through the s o l v e n t f i l l e d porous network. Under s t e a d y s t a t e c o n d i t i o n s , a membrane d e v i c e h a v i n g a s a t u r a t e d drug r e s e r v o i r can m a i n t a i n a c o n s t a n t thermodynamic a c t i v i t y g r a d i e n t a c r o s s the membrane f o r an extended p e r i o d o f t i m e . As a r e s u l t , a c o n s t a n t r a t e o f drug r e l e a s e sometimes r e f e r r e d t o as " z e r o - o r d e r r e l e a s e " o f the d r u g i s e s t a b l i s h e d . The r a t e o f r e l e a s e from such a system i s g e n e r a l l y dependent on the d e v i c e geometry and the n a t u r e , t h i c k n e s s and a r e a o f the membrane, whereas the d u r a t i o n o f the r e l e a s e i s governed by the s i z e o f the drug r e s ervoir. The m a t h e m a t i c a l a n a l y s i s of the k i n e t i c s o f drug r e l e a s e from membrane-reservoir systems has been d i s c u s s e d e x t e n s i v e l y i n the l i t e r a t u r e Q l ,_12) . B e f o r e the e s t a b l i s h m e n t o f a s t e a d y s t a t e , the membrane-reserv o i r d e v i c e w i l l e x h i b i t i n i t i a l r e l e a s e r a t e h i g h e r o r lower t h a n the s t e a d y s t a t e v a l u e , depending on the p r i o r h i s t o r y o f the device. Thus, i m m e d i a t e l y a f t e r f a b r i c a t i o n , a f i n i t e time l a g w i l l be r e q u i r e d t o e s t a b l i s h the s t e a d y - s t a t e c o n c e n t r a t i o n p r o f i l e



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w i t h i n t h e membrane. However, a f t e r t h e d e v i c e i s s t o r e d f o r some time, drug w i l l s a t u r a t e t h e membrane and s u b s e q u e n t l y g i v e r i s e t o an i n i t i a l r e l e a s e r a t e h i g h e r than the s t e a d y s t a t e v a l u e . T h i s i s the s o - c a l l e d b u r s t e f f e c t . The magnitude o f t h e s e t r a n s i e n t e f f e c t s i s r e l a t e d t o t h e drug d i f f u s i o n c o e f f i c i e n t i n t h e membrane and t h e membrane t h i c k n e s s . Membrane-reservoir systems based on s o l u t i o n - d i f f u s i o n mechanism have been u t i l i z e d i n d i f f e r e n t forms f o r the c o n t r o l l e d d e l i v e r y of therapeutic agents. These systems i n c l u d i n g membrane dev i c e s , m i c r o c a p s u l e s , l i p o s o m e s , and h o l l o w f i b r e s have been a p p l i e d to a number o f a r e a s r a n g i n g from b i r t h c o n t r o l , t r a n s d e r m a l d e l i v ery, to cancer therapy. Various polymeric materials i n c l u d i n g s i l i cone r u b b e r , e t h y l e n e v i n y l a c e t a t e copolymers, p o l y u r e t h a n e s , and h y d r o g e l s have been employed i n the f a b r i c a t i o n o f such membraner e s e r v o i r systems ( 1 3 ) . I n a d d i t i o n t o t h e s o l u t i o n - d i f f u s i o n mechanism d i s c u s s e d above, the drug r e l e a s e from a membrane-reservoir d e v i c e can a l s o take p l a c e through an o r i f i c e i n t h e membrane v i a an osmotic pumping mechanism, where a semipermeable membrane such as c e l l u l o s e a c e t a t e i s u t i l i z e d t o r e g u l a t e t h e osmotic p e r m e a t i o n o f water (14) . F o r a system o f c o n s t a n t r e s e r v o i r volume, t h e d e v i c e d e l i v e r s a volume o f drug s o l u t i o n e q u a l t o t h e volume o f o s m o t i c water uptake w i t h i n any g i v e n time i n t e r v a l . The r a t e o f o s m o t i c water i n f l u x and t h e r e f o r e the r a t e o f drug d e l i v e r y by t h e system w i l l be c o n s t a n t as l o n g as a c o n s t a n t thermodynamic a c t i v i t y g r a d i e n t , u s u a l l y d e r i v e d from a s a t u r a t e d r e s e r v o i r w i t h e x c e s s s o l i d , i s m a i n t a i n e d a c r o s s the membrane. However, t h e r a t e d e c l i n e s p a r a b o l i c a l l y once t h e r e s e r v o i r c o n c e n t r a t i o n f a l l s below s a t u r a t i o n . Such an osmotic d e l i v e r y system i s c a p a b l e o f p r o v i d i n g n o t o n l y a p r o l o n g e d z e r o - o r d e r r e l e a s e b u t a l s o a d e l i v e r y r a t e much h i g h e r than t h a t a c h i e v a b l e by the s o l u t i o n - d i f f u s i o n mechanism. The system i s a l s o c a p a b l e o f d e l i v e r i n g drugs w i t h a wide range o f m o l e c u l a r weight and c h e m i c a l c o m p o s i t i o n which a r e n o r m a l l y d i f f i c u l t t o d e l i v e r by the s o l u t i o n - d i f f u s i o n mechanism. The d e l i v e r y r a t e from such d e v i c e s i s g e n e r a l l y r e g u l a t e d by t h e o s m o t i c p r e s s u r e o f the drug c o r e f o r m u l a t i o n and by the water p e r m e a b i l i t y o f the semipermeable membrane. E q u a t i o n s f o r p r e d i c t i n g r e l e a s e r a t e from o s m o t i c pumping d e v i c e s have been d i s c u s s e d by Theeuwes ( 1 5 ) . Matrix

Systems

Matrix Diffusion. H i s t o r i c a l l y , t h e most p o p u l a r d i f f u s i o n - c o n t r o l l e d d e l i v e r y system has been t h e m a t r i x system, such as t a b l e t and g r a n u l e s , where t h e drug i s u n i f o r m l y d i s s o l v e d o r d i s p e r s e d , because o f i t s low c o s t and ease o f f a b r i c a t i o n . However, t h e i n h e r e n t drawback o f t h e m a t r i x system i s i t s f i r s t - o r d e r r e l e a s e behavior with continuously diminishing release rate. This i s a r e s u l t o f t h e i n c r e a s i n g d i f f u s i o n a l r e s i s t a n c e and d e c r e a s i n g a r e a a t t h e p e n e t r a t i n g d i f f u s i o n f r o n t as m a t r i x d i f f u s i o n p r o c e e d s . The k i n e t i c s o f drug r e l e a s e from m a t r i x d e v i c e s c o n t a i n i n g u n i f o r m l y d i s s o l v e d o r d i s p e r s e d drug a r e w e l l documented. In a f l a t s h e e t geometry, where t h e s u r f a c e a r e a i s r e l a t i v e l y c o n s t a n t ,



6

the amount o f drug r e l e a s e f o l l o w s a s q u a r e - r o o t - o f - t i m e r e l a t i o n ship. F o r systems c o n t a i n i n g d i s s o l v e d d r u g , the f r a c t i o n a l drug r e l e a s e M/M^ can be e x p r e s s e d as (11)


M/M^

= (4/A) [ D t / i r ] *

(1)

where M i s the amount o f drug r e l e a s e d a t time t , the t o t a l amount o f drug r e l e a s e d , I the t h i c k n e s s o f the s h e e t , and D the drug d i f f u s i o n c o e f f i c i e n t i n t h e m a t r i x . E q u a t i o n (1) i s a c c u r a t e t o w i t h i n 1% f o r up t o a p p r o x i m a t e l y 60% o f the t o t a l amount r e leased. F o r systems c o n t a i n i n g d i s p e r s e d d r u g , where the drug l o a d i n g per u n i t volume, A, i s g r e a t e r than t h e drug s o l u b i l i t y i n the m a t r i x , C , the drug r e l e a s e k i n e t i c s can be a n a l y z e d by the f a m i l i a r Higucfii equation (16) : M - [C (2A-C ) D t ] * s s

(2)

However, because o f t h e pseudosteady s t a t e assumptions i n v o l v e d , H i g u c h i s e q u a t i o n i s o n l y v a l i d when the drug l o a d i n g i s i n e x c e s s o f t h e drug s o l u b i l i t y ( A » C ) . At the l i m i t of A+C , H i g u c h i s e q u a t i o n g i v e s a r e s u l t 11.31 s m a l l e r than t h e e x a c t s o l u t i o n . Lee ( 4 ) r e c e n t l y p r e s e n t e d 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 f o r t h i s problem which i s u n i f o r m l y v a l i d o v e r a l l A / C v a l u e s : f

1

S

g

M = C (l+H)[Dt/3H] s

i

(3)

where 1

2

H = C ' [5A+(A -C s s

V]-4

When E q u a t i o n (3) i s a p p l i e d t o drug r e l e a s e , the d e v i a t i o n s from the e x a c t r e s u l t s a r e c o n s i s t e n t l y one o r d e r o f magnitude s m a l l e r than those o f H i g u c h i ' s e q u a t i o n . As A/C >1.04, E q u a t i o n (3) has an a c c u r a c y w i t h i n 1% o f the e x a c t s o l u t i o n . T h e r e f o r e , E q u a t i o n (3) i s much more a c c u r a t e than E q u a t i o n ( 2 ) , p a r t i c u l a r l y a t low A/C values. The l a t t e r case o c c u r s q u i t e o f t e n i n d e l i v e r y systems i n v o l v i n g h y d r o p h i l i c polymers and drugs o f h i g h water s o l u b i l i t y . In c a s e s where w e l l - d e f i n e d p o r e s r a n g i n g i n s i z e s from a few hundredths t o s e v e r a l hundred m i c r o n s e x i s t throughout t h e m a t r i x , the k i n e t i c s o f drug r e l e a s e can s t i l l be d e s c r i b e d by E q u a t i o n s (l)-(3) p r o v i d e d t h a t an e f f e c t i v e d i f f u s i o n c o e f f i c i e n t i s u s e d . When the drug d i f f u s i o n o n l y t a k e s p l a c e t h r o u g h the s o l v e n t f i l l e d porous network, the e f f e c t i v e d i f f u s i o n c o e f f i c i e n t i s f u r t h e r r e l a t e d t o the m a t r i x s t r u c t u r e by: D e eff

T

where e i s the p o r o s i t y e x p r e s s e d as the volume f r a c t i o n o f the v o i d space i n the m a t r i x , T the t o r t u o s i t y f a c t o r e x p r e s s e d as the r a t i o of t h e e f f e c t i v e average b a t h l e n g t h i n t h e porous medium t o t h e s h o r t e s t d i s t a n c e measured a l o n g the d i r e c t i o n o f mass f l o w , and D


1. LEE AND GOOD


1


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 i n the pore s o l v e n t . Since the r a t i o e/x i s e q u i v a l e n t t o the f r a c t i o n a l a r e a a v a i l a b l e f o r drug r e l e a s e , an i n c r e a s e i n p o r o s i t y o r a d e c r e a s e i n t o r t u o s i t y w i l l c e r t a i n l y i n c r e a s e the amount of drug r e l e a s e d a t any g i v e n time. Polymer E r o s i o n . The r e l e a s e o f a d i s s o l v e d o r d i s p e r s e d drug from an e r o d i b l e polymer m a t r i x can be c o n t r o l l e d by a v a r i e t y of mechanisms r a n g i n g from h y d r o l y s i s / e n z y m a t i c c l e a v a g e as d i s c u s s e d i n the p r e v i o u s s e c t i o n t o s w e l l i n g and d i s s o l u t i o n . The s i t u a t i o n where polymer e r o d e s by a p u r e l y h e t e r o g e n e o u s p r o c e s s , namely s u r f a c e e r o s i o n , i s o f s p e c i a l i n t e r e s t because the drug r e l e a s e from such d e v i c e s h a v i n g c o n s t a n t geometry (sheet geometry) w i l l be o f c o n s t a n t r a t e ( 2 ) . U n f o r t u n a t e l y , the c o r r e s p o n d i n g r e l e a s e s from b o t h the c y l i n d r i c a l and s p h e r i c a l g e o m e t r i e s a l l e x h i b i t d e c r e a s i n g r a t e s w i t h time ( 1 7 ) . In c a s e s where the d i f f u s i o n a l c o n t r i b u t i o n i s p r e s e n t i n a d d i t i o n to s u r f a c e e r o s i o n , i t has been shown ( 4 ) t h a t the r e l e a s e from sheet geometry g e n e r a l l y s t a r t s w i t h t y p i c a l f i r s t o r d e r k i n e t i c s then s h i f t s toward z e r o - o r d e r k i n e t i c s . Apparently, a synchronizat i o n o f b o t h the d i f f u s i o n and e r o s i o n f r o n t v e l o c i t i e s a t l a r g e time g i v e s r i s e t o the o b s e r v e d c o n s t a n t r a t e of drug r e l e a s e . Rec e n t l y , Lee (5)has shown t h a t by b u i l d i n g i n a n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n , a v a r i e t y of r e l e a s e p r o f i l e s r a n g i n g from z e r o - o r d e r to p u l s a t i l e d e l i v e r y can be a c h i e v e d from s u r face erosion c o n t r o l l e d matrices i n various geometries. Geometry F a c t o r s . To overcome the i n h e r e n t f i r s t - o r d e r r e l e a s e b e h a v i o r w i t h c o n t i n u o u s l y d i m i n i s h i n g r e l e a s e r a t e from m a t r i x s y s tems, geometry f a c t o r s have been u t i l i z e d to compensate f o r the i n c r e a s i n g d i f f u s i o n a l d i s t a n c e and d e c r e a s i n g a r e a a t the p e n e t r a t i n g d i f f u s i o n f r o n t g e n e r a l l y e n c o u n t e r e d i n m a t r i x systems. A h e m i s p h e r i c a l polymer m a t r i x t h a t i s c o a t e d on a l l s u r f a c e s w i t h an impermeable c o a t i n g e x c e p t f o r an a p e r t u r e i n the c e n t e r f a c e has been demonstrated t o p r o v i d e near c o n s t a n t r a t e r e l e a s e p r o f i l e s (18). A n o t h e r approach c o n s i s t s o f a c y l i n d e r w i t h impermeable w a l l and a c a v i t y h a v i n g a c i r c u l a r s e c t o r c r o s s s e c t i o n . The c e n t e r o f the c i r c u l a r s e c t o r l i e s o u t s i d e the c y l i n d e r , t h e r e b y p r o d u c i n g a s l i t f o r d r u g r e l e a s e from the drug c o n t a i n i n g m a t r i x i n the c a v i t y . The r e l e a s e p r o f i l e s from t h i s system a l s o show a subs t a n t i a l c o n s t a n t r a t e r e g i o n (19,20). I t i s c l e a r that, i n both systems, the i n c r e a s e i n d i f f u s i o n a l d i s t a n c e and c o n s e q u e n t l y the d e c r e a s e i n d i f f u s i o n r a t e have been b a l a n c e d by the i n c r e a s e i n a r e a a t the d i f f u s i o n f r o n t t h e r e b y g i v i n g r i s e t o a near c o n s t a n t rate region. Polymer S w e l l i n g . S w e l l i n g phenomena are g e n e r a l l y e n c o u n t e r e d i n b o t h the h y d r o p h i l i c and h y d r o p h o b i c polymer m a t r i c e s d u r i n g the r e l e a s e of e n t r a p p e d water s o l u b l e drug i n an aqueous environment. I f the polymer i s c r o s s l i n k e d e i t h e r c h e m i c a l l y t h r o u g h c o v a l e n t b o n d i n g or p h y s i c a l l y t h r o u g h e x t e n s i v e entanglement or c r y s t a l l i t e f o r m a t i o n , the s w e l l i n g w i l l c o n t i n u e to some e q u i l i b r i u m s t a t e a t which the e l a s t i c and s w e l l i n g (or o s m o t i c ) f o r c e s b a l a n c e each other.



8

CONTROLLED-RELEASE

TECHNOLOGY

Depending on the r e l a t i v e magnitude o f the r a t e o f polymer s w e l l i n g t o the r a t e o f drug d i f f u s i o n , v a r i o u s r e l e a s e p r o f i l e s may be p o s s i b l e . The s i t u a t i o n where the polymer s t r u c t u r a l r e a r r a n g e ment t a k e s p l a c e r a p i d l y i n r e s p o n s e to the s w e l l i n g s o l v e n t as compared to drug d i f f u s i o n g e n e r a l l y l e a d s to t y p i c a l F i c k i a n d i f f u s i o n c h a r a c t e r i s t i c s and the s o - c a l l e d f i r s t - o r d e r r e l e a s e behavior. The case of p a r t i c u l a r i n t e r e s t i s the g l a s s y h y d r o g e l system where, upon water p e n e t r a t i o n , a slow m a c r o m o l e c u l a r r e l a x a t i o n p r o c e s s a t the g l a s s / r u b b e r y s w e l l i n g f r o n t i n a d d i t i o n to d i f f u s i o n p r o v i d e s an a d d i t i o n a l mechanism to a l t e r the r e l e a s e k i n e t i c s from the i n h e r e n t f i r s t - o r d e r b e h a v i o r . The p r o s p e c t o f h a v i n g z e r o o r d e r r e l e a s e k i n e t i c s from g l a s s y polymer m a t r i c e s v i a such a s w e l l i n g c o n t r o l l e d mechanism has s t i m u l a t e d an i n c r e a s i n g number of r e s e a r c h s t u d i e s , p u b l i c a t i o n s and p a t e n t s i n t h i s a r e a i n v o l v i n g the c o n t r o l l e d - r e l e a s e of b o t h s m a l l m o l e c u l a r weight and macrom o l e c u l a r b i o a c t i v e compounds (21-28). M e c h a n i s t i c a l l y , as water p e n e t r a t e s a g l a s s y h y d r o g e l m a t r i x c o n t a i n i n g d i s s o l v e d o r d i s p e r s e d d r u g , the polymer s w e l l s and i t s g l a s s t r a n s i t i o n temperature i s l o w e r e d , and the d i s s o l v e d drug d i f f u s e s through the s w o l l e n r u b b e r y phase i n t o the e x t e r n a l r e l e a s i n g medium. At the same t i m e , a sharp p e n e t r a t i n g s o l v e n t f r o n t s e p a r a t i n g the g l a s s y from the r u b b e r y phase i n a d d i t i o n t o volume s w e l l i n g i s o b s e r v e d d u r i n g the i n i t i a l s t a g e of the dynamic s w e l l ing process. Depending on the r e l a t i v e magnitude o f the r a t e of polymer r e l a x a t i o n a t the p e n e t r a t i n g s o l v e n t f r o n t and the r a t e of d i f f u s i o n o f the d i s s o l v e d d r u g , the drug r e l e a s e b e h a v i o r may range from f i r s t to z e r o - o r d e r (21). V a r i o u s a n a l y s e s and c r i t e r i a have been r e p o r t e d i n the l i t e r a t u r e f o r p r e d i c t i n g whether drug r e l e a s e from s w e l l i n g - c o n t r o l l e d polymer m a t r i c e s w i l l be f i r s t o r z e r o - o r d e r ( d i f f u s i o n o r r e l a x a t i o n - c o n t r o l l e d ) (29). However, they have been s u c c e s s f u l o n l y f o r l i m i t e d s i t u a t i o n s o f v e r y low drug l o a d i n g . In g e n e r a l , the drug l o a d i n g l e v e l has a d e f i n i t i v e e f f e c t on the r e l e a s e k i n e t i c s from s w e l l i n g - c o n t r o l l e d polymer m a t r i c e s . E x p e r i m e n t a l e v i d e n c e s have shown t h a t the p r e s e n c e of an a d d i t i o n a l component, namely the water s o l u b l e d r u g , a l t e r s b o t h the s w e l l i n g o s m o t i c p r e s s u r e and the a s s o c i a t e d time-dependent r e l a x a t i o n o f the h y d r o g e l network d u r i n g the s i m u l t a n e o u s a b s o r p t i o n o f water and d e s o r p t i o n o f drug ( 2 5 ) . As a r e s u l t , the drug r e l e a s e and s o l v e n t f r o n t p e n e t r a t i o n a r e o b s e r v e d t o behave more F i c k i a n as drug l o a d i n g l e v e l i n c r e a s e s . Such t r a n s i t i o n can be c o n s i d e r e d as a change of r e l a t i v e importance o f the d i f f u s i o n p r o c e s s v e r s u s the polymer r e l a x a t i o n as a f u n c t i o n of drug l o a d i n g . C o n c e n t r a t i o n D i s t r i b u t i o n . D e s p i t e the t h e o r e t i c a l p r o s p e c t o f having a t o t a l l y r e l a x a t i o n - c o n t r o l l e d s i t u a t i o n thereby achieving z e r o - o r d e r r e l e a s e from a g l a s s y polymer m a t r i x , h y d r o g e l s w i t h pure r e l a x a t i o n - c o n t r o l l e d (Case I I ) s w e l l i n g k i n e t i c s a r e y e t to be demonstrated experimentally. In a d d i t i o n , the i n e v i t a b l e geometry l i m i t a t i o n s and d e v i a t i o n s from r e l a x a t i o n - c o n t r o l l e d k i n e t i c s a t h i g h e r drug l o a d i n g l e v e l s f u r t h e r i m p a i r the f l e x i b i l i t y i n a l t e r ing the r e l e a s e k i n e t i c s i n such systems. T h i s d i f f i c u l t y can be overcome by a r e c e n t l y r e p o r t e d , n o v e l approach t o c o n s t a n t r a t e of drug r e l e a s e from g l a s s y h y d r o g e l m a t r i c e s v i a an immobolized



1.

LEE AND GOOD


9

n o n - u n i f o r m drug c o n c e n t r a t i o n d i s t r i b u t i o n (30>3^) · Hydrogel polymers a r e p a r t i c u l a r l y s u i t a b l e f o r t h i s a p p l i c a t i o n because they are g l a s s y i n the d e h y d r a t e d s t a t e c a p a b l e o f i m m o b o l i z i n g any n o n - u n i f o r m drug d i s t r i b u t i o n i n t r o d u c e d p r i o r t o t h e d e h y d r a t i o n step. The drug r e l e a s e w i l l n o t o c c u r u n t i l t h e h y d r o g e l i s s w o l l e n by water a t the time o f u s e . As a r e s u l t o f t h i s s t u d y , the e f f e c t o f n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n on t h e k i n e t i c s o f drug r e l e a s e from polymer m a t r i c e s o f d i f f e r e n t g e o m e t r i e s has been a n a l y z e d i n d e t a i l (5). Concentration p r o f i l e s capable of generating zero-order r e l e a s e c h a r a c t e r i s t i c s have a l s o been i d e n t i f i e d . The impact o f t h i s approach i s r e a l l y p r o f o u n d s i n c e t h e concept o f u t i l i z i n g n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n as a mechanism f o r r e g u l a t i n g drug r e l e a s e from b o t h d i f f u s i o n - c o n t r o l l e d and s u r f a c e e r o s i o n - c o n t r o l l e d polymer m a t r i c e s o f f e r s a unique o p p o r t u n i t y t o a c h i e v e programmable ( i n c l u d i n g z e r o - o r d e r and p u l s a t i l e ) drug d e l i v e r y i n meeting a s p e c i f i c t e m p o r a l t h e r a p e u t i c requirement. T h i s i s p a r t i c u l a r l y a t t r a c t i v e i n view o f t h e e x p e r i m e n t a l f l e x i b i l i t y i n a c h i e v i n g e s s e n t i a l l y an u n l i m i t e d number o f n o n - u n i f o r m d r u g c o n c e n t r a t i o n d i s t r i b u t i o n i n polymer systems. U n l i k e membrane-reservoir systems, t h e c o n c e n t r a t i o n d i s t r i b u t i o n approach does n o t r e q u i r e a s a t u r a t e d r e s e r v o i r and a r a t e - c o n t r o l l i n g membrane t o a c h i e v e a c o n s t a n t r a t e o f d r u g r e l e a s e . I n a d d i t i o n , t h e o n s e t o f c o n s t a n t - r a t e r e l e a s e i n t h e p r e s e n t approach can be almost i n s t a n t a n e o u s and the c o n s t a n t - r a t e r e l e a s i n g p e r i o d can be r e l a t i v e l y s h o r t . These a r e d i f f i c u l t t o a c h i e v e i n convent i o n a l membrane-reservoir systems. Biopharmaceutical Considerations The most i m p o r t a n t a t t r i b u t e o f a c o n t r o l l e d r e l e a s e drug d e l i v e r y system i s i t s c a p a b i l i t y t o m a i n t a i n a t h e r a p e u t i c a l l y e f f e c t i v e r a t e o f drug d e l i v e r y over a r e a s o n a b l y l o n g p e r i o d o f time. The d u r a t i o n o f such c o n t r o l l e d d e l i v e r y must be c o m p a t i b l e w i t h p h y s i o l o g i c a l c o n s t r a i n t s and the r o u t e o f a d m i n i s t r a t i o n . F o r example, w h i l e a d u r a t i o n o f s e v e r a l months may be a p p r o p r i a t e f o r a polymer i m p l a n t , i t i s much t o o l o n g a time frame t o c o n s i d e r f o r an o r a l dosage form. S i m i l a r l y , a c o n s t a n t r a t e o f drug d e l i v e r y may p r o v i d e l i t t l e r e a l advantage over w e l l c o n t r o l l e d f i r s t - o r d e r r e l e a s e under c e r t a i n b i o p h a r m a c e u t i c c o n d i t i o n s , e s p e c i a l l y when the b i o l o g i c a l h a l f - l i f e o f t h e drug i s l o n g . I n some s i t u a t i o n s , an o s c i l l a t o r y o r p u l s a t i l e drug r e l e a s e may be needed i n o r d e r t o simulate i n v i v o s e c r e t o r y p a t t e r n s or to avoid t a c h y p h y l a x i s . In the f o l l o w i n g s e c t i o n s , c r i t e r i a f o r system s e l e c t i o n and r e l e v a n t b i o p h a r m a c e u t i c a l c o n s i d e r a t i o n s w i l l be b r i e f l y d i s c u s s e d w i t h i n the r e a l m o f o r a l and t r a n s d e r m a l d e l i v e r y systems. Similar conside r a t i o n s can c e r t a i n l y be extended t o o t h e r t y p e s o f d e l i v e r y systems. O r a l D e l i v e r y Systems. The o r a l r o u t e o f drug a d m i n i s t r a t i o n has been t h e most p o p u l a r one, however, i t i s n o t w i t h o u t problems and constrains. F i r s t o f a l l , t h e t o t a l g a s t r o i n t e s t i n a l r e s i d e n c e time l i m i t s t h e time frame o r "window" f o r o r a l a b s o r p t i o n . The



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s i t u a t i o n can become more c o m p l i c a t e d i f the drug i n q u e s t i o n i s o n l y absorbed i n c e r t a i n segments of the GI t r a c t ( 3 2 ) . Realizing the p o t e n t i a l i n t e r - s u b j e c t v a r i a b i l i t y and the e f f e c t of food on GI r e s i d e n c e time and m o b i l i t y p a t t e r n s (33,34), a r e a s o n a b l e d u r a t i o n c o n s t r a i n i n the GI t r a c t i s a p p r o x i m a t e l y 24 hours t a k i n g i n t o c o n s i d e r a t i o n the g a s t r i c emptying mechanism and i t s d u r a t i o n as w e l l as s m a l l and l a r g e i n t e s t i n a l t r a n s i t t i m e s . A n o t h e r time c o n s t r a i n i s a s s o c i a t e d w i t h drug a b s o r p t i o n t h r o u g h the GI mucosa i n t o the g e n e r a l h e p a t i c c i r c u l a t i o n . In o r d e r to c o n t r o l the del i v e r y of drug t o the u l t i m a t e t a r g e t o r g a n v i a the g e n e r a l c i r c u l a t i o n , i t i s e s s e n t i a l t o have the system r e l e a s i n g i t s c o n t e n t a t a s l o w e r r a t e than the p h y s i o l o g i c a l a b s o r p t i o n r a t e . In a d d i t i o n , when the gut w a l l and f i r s t pass l i v e r m e t a b o l i s m a r e s i g n i f i c a n t , the r a t e of drug d e l i v e r y to the GI t r a c t may have p r o f o u n d e f f e c t s on the amount o f unchanged drug which r e a c h e s the p e r i p h e r a l c i r c u l a t i o n and the r a t e which m e t a b o l i s m t a k e s p l a c e . Understandably, the e x c r e t i o n r a t e o r c l e a r a n c e o f the drug from p e r i p h e r a l c i r c u l a t i o n and/or any t i s s u e compartments w i l l a l s o a f f e c t the s e l e c t i o n and d e s i g n of the drug d e l i v e r y system. For the r a t i o n a l d e s i g n o f a c o n t r o l l e d - r e l e a s e o r a l d e l i v e r y system, one o b v i o u s l y would have t o take i n t o c o n s i d e r a t i o n pharmac o k i n e t i c r a t e p a r a m e t e r s f o r the a b s o r p t i o n , d i s t r i b u t i o n , and e l i m i n a t i o n o f a s p e c i f i c drug i n q u e s t i o n as w e l l as the drug del i v e r y r a t e p r o f i l e from the d e l i v e r y system. In the l a t t e r c a s e , p r a c t i c a l l i m i t a t i o n s i n d e l i v e r y system d e s i g n such as f i n i t e t o t a l dose, d e c r e a s i n g r e s e r v o i r c o n c e n t r a t i o n s , and/or i n c r e a s i n g d i f f u s i o n a l r e s i s t a n c e would have t o be t a k e n i n t o a c c o u n t . Such an approach has r e c e n t l y been a p p l i e d to the d e s i g n o f c o n t r o l l e d - r e l e a s e o r a l d e l i v e r y systems (11,35) . E x c e l l e n t agreement has been demonstrated between e x p e r i m e n t a l d a t a and p r e d i c t e d performance b o t h i n v i t r o and i n v i v o . T r a n s d e r m a l D e l i v e r y Systems. T r a n s d e r m a l d e l i v e r y of drugs over extended p e r i o d s of time f o r s y s t e m i c t h e r a p y has r e c e i v e d significant attention. The importance and f u t u r e p r o s p e c t s o f t h i s f i e l d are f u r t h e r r e f l e c t e d i n the s e c t i o n on T r a n s d e r m a l and T r a n s m u c o s a l D e l i v e r y Systems ( C h a p t e r s 17-23). I n t a c t human s k i n , once thought t o be an impermeable b a r r i e r , was r e a l i z e d as a p o t e n t i a l p o r t a l o f e n t r y f o r s y s t e m i c drug t h e r a p y o n l y r e c e n t l y . U n l i k e the GI t r a c t , the p e r f u s i o n o f s k i n s t r u c t u r e s i s s u p p l i e d by post-hepatic blood flow. T h e r e f o r e , drugs absorbed through the s k i n do not undergo e x t e n s i v e f i r s t pass m e t a b o l i s m . A l t h o u g h p r o t e i n b i n d i n g of drugs (36) as w e l l as a c t i v e m e t a b o l i s m i n s k i n (37) have been r e p o r t e d , they are g e n e r a l l y minor i n e f f e c t s compared t o t h a t due t o l i v e r m e t a b o l i s m . A d d i t i o n a l advantages to t r a n s d e r m a l d e l i v e r y can be r e a l i z e d from i t s i n h e r e n t n o n - i n v a s i v e c h a r a c t e r as w e l l as the a b i l i t y t o r a p i d l y remove the dosage form a t any t i m e , a s i g n i f i c a n t s a f e t y f e a t u r e not a v a i l a b l e i n o r a l o r p a r e n t e r a l routes of a d m i n i s t r a t i o n . The upper l a y e r s of e p i d e r m i s , the s t r a t u m corneum, i s a p r i n c i p a l b a r r i e r to t r a n s d e r m a l drug d e l i v e r y . I t c o n s i s t s of a h e t e r o g e n e o u s s t r u c t u r e made up o f k e r a t i n i z e d c e l l s and l i p i d s . Drug p e r m e a t i o n i s b e l i e v e d t o o c c u r by e i t h e r p o l a r o r l i p o p h i l i c pathways depending on the h y d r o p h i l i c i t y o r l i p o p h i l i c i t y of the



1.

L E E A N D GOOD


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drug (38). The fundamental q u e s t i o n t o be answered b e f o r e d e s i g n i n g a t r a n s d e r m a l system i s whether d e l i v e r y - r a t e c o n t r o l must be p a r t of t h e system o r whether i t i s more d e s i r a b l e s i m p l y t o a l l o w t h e s k i n t o s e r v e as t h e p r i n c i p l e b a r r i e r t o t r a n s p o r t . In e i t h e r c a s e , r a t e o f drug a b s o r p t i o n i s dependent on b o t h s k i n permeability and t h e 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 system. The degree o f c o n t r o l d e s i r e d i s d i c t a t e d by t h e p h a r m a c o l o g i c a l p r o f i l e o f t h e drug. A good comparison can be i l l u s t r a t e d by t h e d i f f e r e n c e i n d e s i g n c o n s i d e r a t i o n s between t r a n s d e r m a l s c o p o l a m i n e and t r a n s dermal n i t r o g l y c e r i n systems (11,39). Scopolamine i s a p o t e n t drug w i t h modest s k i n p e r m e a b i l i t y and a wide range o f s i d e e f f e c t s associated with i n c r e a s i n g blood l e v e l s . Therefore, i n order to t r e a t motion s i c k n e s s without producing s i d e e f f e c t s , i t i s n e c e s s a r y t o produce t h e r a p e u t i c a l l y e f f e c t i v e i n p u t r a t e by p r e c i s e l y c o n t r o l l i n g t h e r a t e a t which i t i s t r a n s p o r t e d from t h e system t o t h e s k i n . I n c o n t r a s t , n i t r o g l y c e r i n has a f a i r l y wide t h e r a p e u t i c i n d e x , and a s u b s t a n t i a l s k i n p e r m e a b i l i t y w i t h l a r g e v a r i a b i l i t y among i n d i v i d u a l s . Given n i t r o g l y c e r i n ' s short h a l f l i f e , i t s i n p u t r a t e s h o u l d be m a i n t a i n e d a t a r e a s o n a b l y h i g h l e v e l i n order t o m a i n t a i n e f f i c a c y . T h e r e f o r e , the c o n t r o l of n i t r o g l y c e r i n d e l i v e r y r a t e i s m e r e l y t o ensure an upper bound b e i n g s e t by the system f o r i n d i v i d u a l s even w i t h extreme s k i n permeability. Such d e s i g n c r i t e r i a have been s u c c e s s f u l l y u t i l i z e d i n c o m m e r c i a l l y a v a i l a b l e m e m b r a n e - r e s e r v o i r type o f t r a n s d e r m a l d e l i v e r y systems f o r s c o p o l a m i n e , n i t r o g l y c e r i n , and more r e c e n t l y , e s t r a d i o l (40,41).

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10. Petersen, R.V.; Anderson, J.H.; Fang, S.M.; Feijen, J . ; Gregonis, D.E.; Kim, S.W. Polym. Prepr. 1979, 20, 20. 11. Good, W.R.; Lee, P.I. In "Medical Applications of Sustained Release" Langer, R.S.; Wise, D.L., Eds.; CRC Press:Boca Raton, FL, 1984; pp. 1. '


12. Baker, R.W.; Lonsdale, H.K. In "Controlled Release of Biologically Active Agents"' Tanquary, A.C.; Lacey, R.E., Eds.; ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY SERIES NO. 47; Plenum:New York, NY, 1974; pp.15. 13. Kim, S.W.; Petersen, R.; Feijen, J. Drug Design 1980, 10, 193. 14. Theeuwes, F. In "Controlled Release Technologies:Methods, Theory and Applications", Kydonieus, A.F., Ed.; CRC Press:Boca Raton, FL, 1980; pp. 195. 15. Theeuwes, F. J. Pharm. Sci. 1975, 64, 1987. 16. Higuchi, T. J. Pharm. Sci. 1961, 50, 874. 17. Hopfenberg, H.B. In "Controlled Release Polymeric Formulations"; Paul, D.R.; Harris, F.W., Eds.; ACS SYMPOSIUM SERIES NO. 33; American Chemical Society:Washington, D.C., 1976; pp. 26. 18. Hsieh, D.S.T.; Rhine, W.D.; Langer, R. J. Pharm. Sci. 1983, 72, 17. 19. Brooke, D.; Washkuhn, R.I. J. Pharm. Sci. 1977, 66, 159. 20. Lipper, R.A.; Higuchi, W.I. J. Pharm. Sci. 1977, 66, 163. 21. Lee, P.I. J. Controlled Release 1985, 2, 277. 22. Pedley, D.G.; Skelly, P.J.; Tighe, B.J. Br. Polym. J. 1980, 12, 99. 23.

Speiser, P. U.S. Patent 3,390,050, 1968.

24. Mueller, K.F.; Heiber, S.J.; Plankl, W.L. U.S. Patent 4,244,427, 1980. 25. Lee, P.I. Polym. Commun. 1983, 24, 45. 26. Good, W.R.; Mueller, K.F. In "Controlled Release of Bioactive Materials"' Baker, R., Ed.; Academic:New York, NY, 1980; pp. 155. 27. Mueller, K.F.; Good, W.R. U.S. Patent 4,177,056, 1979. 28. Peppas, N.A. "Hydrogels in Medicine and Pharmacy"; CRC Press: Boca Raton, Fl, 1987; Vol. I-III.


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LEE AND GOOD


29. Korsmeyer, R.W.; Peppas, N.A. In "Controlled Release Delivery Systems"; Roseman, T.J.; Mansdorf, S.Z., Eds.; Marcel Dekker, NY, 1983; pp. 77. 30. Lee, P.I. Polymer 1984, 25, 973. 31. Lee, P.I.

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32. Morrison, A.B.; Perusse, C.B.; Campbell, J.A. New Engl. J. Med. 1960, 263, 115. 33.

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35. Good, W.R.; Leeson, L.J.; Zak, S.L.; Wagner, W.E.; Meeker, J.B.; Arnold, J.D. Br. J. Clin. Pharm. 1985, 19, 2315. 36.

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37. Ando, H.Y.; Ho, N.F.; Higuchi, W.I. J. Pharm. Sci. 1977, 66, 1525. 38. Knutson, K.; Krill, S.L.; Lambert, W.J.; Higuchi, W.I. Proc. 13th Int. Symp. Cont. Rel. Bioac. Mater., 1986, p. 199. 39.

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40. Good, W.R.; Powers, M.S.; Campbell, P.; Schenkel, L. trolled Release 1985, 2, 89. 41.

J. Con

Schenkel, L.; Barlier, D.; Riera, M.; Barner, A. J. Controlled Release 1986, 4, 195.

RECEIVED May 18, 1987


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