Polymeric Delivery Systems - ACS Publications - American Chemical

Chapter 2

Polymeric Drug Delivery Systems An

Overview

Patrick Sinko and Joachim 1

Downloaded by MONASH UNIV on October 29, 2012 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch002

1

Kohn

2,3

Department of Pharmaceutics, College of Pharmacy, and Department of Chemistry, Rutgers University, New Brunswick, N J 08903 2

A l t h o u g h already in 1971 Yolles et al. discussed the design of polymeric devices for the delivery of drugs (1) and a patent was filed by Boswell a n d Scribner on the use of polylactic acid in drug delivery systems (2), two widely cited papers by Yolles et a l . from the year 1 9 7 3 (3,4) are often regarded as the s t a r t i n g p o i n t of the development of polymeric drug delivery systems. F r o m the modest beginnings i n 1973 when drugs were simply mixed into a polymeric matrix, a n avalanche of theoretical and practical advances led to the rapid development of a large number of distinct system configurations a n d device designs. Today, drug delivery devices can be conveniently divided into two large categories relating to "controlled drug release systems" and "targeted drug delivery systems." T h e definition of controlled release versus targeted d r u g delivery is based on the relationship between the site of d r u g release a n d the site of drug action. Controlled release systems deliver drug into the systemic circulation at a predetermined rate. T h u s , the site of d r u g release and the site of drug action are not the same. Targeted delivery systems, on the other hand, release medications at or near the site of action. A n advantage of targeted drug delivery is that high local concentrations of drug c a n be achieved, since the d r u g is delivered p r e d o m i n a n t l y to the site of action rather t h a n being d i s t r i b u t e d throughout the whole body. It is noteworthy that there is surprisingly little practical overlap between "controlled release" and "targeted delivery". For the successful development of a controlled release device, a water insoluble, inert polymer is u s u a l l y needed. Device formulation is predominantly a n engineering p r o b l e m r e q u i r i n g detailed knowledge of p h y s i c o c h e m i c a l p h e n o m e n a s u c h as diffusion, swelling, erosion a n d / o r 3

Corresponding author: Department of Chemistry, Rutgers University, P.O. Box 939, Piscataway, NJ 08855-0939

0097-6156/93/0520-0018$07.00/0 © 1993 American Chemical Society

In Polymeric Delivery Systems; El-Nokaly, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.


2. SINKO AND K O H N

Polymeric Drug Delivery Systems: An Overview

d e g r a d a t i o n . O n t h e o t h e r h a n d , for t h e s u c c e s s f u l d e v e l o p m e n t of a t a r g e t e d ( p e n d e n t c h a i n type) d e l i v e r y s y s t e m a w a t e r s o l u b l e , e a s i l y functionalized polymer is u s u a l l y needed a n d a n intimate knowledge of t h e b i o l o g i c a l a n d / o r p h y s i o l o g i c a l i n t e r a c t i o n s t h a t l e a d to t h e d e s i r e d t a r g e t i n g effect i s i n d i s p e n s a b l e . A s a scientific field, the s c i e n c e of d r u g delivery is h i g h l y i n t e r d i s c i p l i n a r y . A l m o s t a l l o f t h e m a j o r d i s c i p l i n e s r e l a t e d to c h e m i s t r y , biology, p h a r m a c e u t i c s , pharmacology, a n d medicine have a b e a r i n g o n d r u g d e l i v e r y ( F i g u r e 1). T h i s d i v e r s i t y m a k e s i t a l m o s t i m p o s s i b l e t o c o l l e c t a set of r e s e a r c h p a p e r s t h a t i s r e p r e s e n t a t i v e of t h e f i e l d a s a w h o l e a n d , at the same time, i n t e r n a l l y c o h e s i v e . This point is c l e a r l y i l l u s t r a t e d b y the s e l e c t i o n of m a n u s c r i p t s i n c l u d e d i n t h i s v o l u m e w h i c h h a s b e e n d e s i g n e d to p r o v i d e a r e p r e s e n t a t i v e o v e r v i e w of the w i d e range of a p p l i c a t i o n s of p o l y m e r i c delivery s y s t e m s . P a r t i c u l a r l y noteworthy is the c e n t r a l role o c c u p i e d b y p o l y m e r c h e m i s t r y w i t h i n the field of " d r u g delivery". The rapid advances m a d e i n the d e s i g n a n d d e v e l o p m e n t of n e w d r u g delivery s y s t e m s were fueled p r e d o m i n a n t l y by advances m a d e i n polymer chemistry. Implantable, or insertable controlled release devices, targeted d r u g carriers, and transdermal systems all contain polymeric materials t h a t w e r e o f t e n s p e c i f i c a l l y f o r m u l a t e d for t h e s e a p p l i c a t i o n s . O n t h e o t h e r h a n d , t h e o b v i o u s n e e d to f i n d n e w m a t e r i a l s for t h e g r o w i n g r e s e a r c h effort i n d r u g d e l i v e r y p r o v i d e d t h e i m p e t u s ( a n d o f t e n t h e f i n a n c i a l s u p p o r t ) for t h e d e v e l o p m e n t of a w i d e r a n g e of n e w , degradable polymers. A m o r e d e t a i l e d overview of s o m e p o l y m e r s u s e d for d r u g a n d p e p t i d e d e l i v e r y i s p r o v i d e d i n a s e p a r a t e c h a p t e r . O v e r t h e l a s t 10 to 2 0 y e a r s , t h e f i e l d of d r u g d e l i v e r y h a s g r o w n a n d progressed at a t r u l y r e m a r k a b l e rate. T h i s g r o w t h w a s fueled not only by a convincing need b u t also by powerful commercial i n t e r e s t s . T h e a b i l i t y to m a i n t a i n m a r k e t s h a r e s a n d p r o l o n g t h e effective p e r i o d o f p a t e n t p r o t e c t i o n for a g i v e n d r u g b y r e f o r m u l a t i o n of the d r u g as a "controlled release" or "targeted delivery" s y s t e m h a s b e e n r e c o g n i z e d a s a n i m p o r t a n t r e a s o n for t h e i n t e r e s t o f t h e p h a r m a c e u t i c a l i n d u s t r y i n advanced d r u g delivery devices. Thus, s i g n i f i c a n t c o n t r i b u t i o n s to t h e d e v e l o p m e n t o f a d v a n c e d d r u g d e livery were made by researchers associated w i t h i n d u s t r i a l research p r o g r a m s a n d c l o s e c o l l a b o r a t i v e efforts b e t w e e n s c i e n t i s t s i n a c a d e m i a a n d i n d u s t r y have a l w a y s b e e n a c h a r a c t e r i s t i c of t h e field. T h i s i s c l e a r l y d e m o n s t r a t e d b y t h e large p r o p o r t i o n of i n d u s t r i a l contributions included i n this volume. C o n t r o l l e d D r u g Release T h e o b j e c t i v e i n t h e d e s i g n o f a c o n t r o l l e d d r u g r e l e a s e s y s t e m i s to release a p h a r m a c o l o g i c a l l y active agent i n a p r e d e t e r m i n e d , predictable, a n d reproducible fashion. Originally, the u n d e r l y i n g rationa l e o f c o n t r o l l e d r e l e a s e f o r m u l a t i o n s w a s t h a t a d r u g i s m o r e effective a n d e x h i b i t s l e s s s i d e effects w h e n t h e d r u g c o n c e n t r a t i o n i n c i r c u l a t i o n i s k e p t c o n s t a n t at s o m e o p t i m u m level for p r o l o n g e d


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POLYMERIC DELIVERY SYSTEMS

p e r i o d s of t i m e . T h i s r a t i o n a l e c a n b e i l l u s t r a t e d b y a g r a p h s h o w i n g t h e e x p e c t e d d r u g c o n c e n t r a t i o n p r o f i l e s for a n u m b e r o f d i f f e r e n t m e t h o d s o f d r u g a d m i n i s t r a t i o n ( F i g u r e 2). B r i e f l y , t h e d r u g c o n c e n t r a t i o n i n b l o o d r e a c h e s a m a x i m u m v e r y r a p i d l y after a d m i n i s t r a t i o n o f a s t a n d a r d d o s a g e f o r m a n d t h e n d e c r e a s e s to a m i n i m u m , a t w h i c h point repeated administration becomes necessary. Often the initial m a x i m u m c o n c e n t r a t i o n is above the t h e r a p e u t i c a l l y desirable level, i n c r e a s i n g t h e r i s k of s i d e effects. O n t h e o t h e r h a n d , t h e m i n i m u m c o n c e n t r a t i o n m a y b e b e l o w t h e t h e r a p e u t i c a l l y effective l e v e l . I n t h i s way, s t a n d a r d dosage forms c a n result i n a d r u g regimen i n w h i c h the p a t i e n t o s c i l l a t e s b e t w e e n a l t e r n a t i n g p e r i o d s of d r u g o v e r d o s e a n d d r u g inefficacy. C o n t r o l l e d release systems, ideally, s m o o t h the p e a k s a n d valleys i n the drug concentration i n blood providing a more effective d r u g r e g i m e n . Researchers soon realized that constant d r u g concentrations are not necessarily the best treatment regimen. D u r i n g the 1980s, d i a b e t e s , w h e r e w i d e l y fluctuating levels o f i n s u l i n a r e r e q u i r e d to m i m i c the n a t u r a l biofeedback m e c h a n i s m s , became a widely investigated " t e s t c a s e " for t h e a p p l i c a t i o n of a m o d u l a t e d r e l e a s e s y s t e m . T h u s , t h e t e r m " c o n t r o l l e d r e l e a s e " w a s e x p a n d e d to i n c l u d e a l s o t h o s e s y s t e m s t h a t w e r e i n t e n t i o n a l l y d e s i g n e d to p r o v i d e n o n l i n e a r r e l e a s e characteristics. In this context, external s t i m u l i s u c h as temperature c h a n g e s (5), p H c h a n g e s (6), m a g n e t i c (7) a n d e l e c t r i c f i e l d s (8), u l t r a s o u n d (9), m i c r o w a v e i r r a d i a t i o n (10), a n d v i s i b l e l i g h t (11) w e r e u s e d to p r o d u c e c h a n g e s i n t h e r a t e o f d r u g r e l e a s e . I n m a n y cases, these studies explored whether external s t i m u l i c a n imitate n a t u r a l b i o f e e d b a c k m e c h a n i s m s . T h i s c h a l l e n g i n g l i n e of r e s e a r c h m a y l e a d u l t i m a t e l y to c o n t r o l l e d d r u g r e l e a s e s y s t e m s t h a t r e l e a s e d r u g s i n r e s p o n s e to a s p e c i f i c b i o l o g i c a l p r o c e s s . Possible Sites of A c t i o n for C o n t r o l l e d Release S y s t e m s . A d v a n c e d c o n t r o l l e d r e l e a s e s y s t e m s offer a s i g n i f i c a n t d e g r e e of f r e e d o m i n t h e c h o i c e of t h e i r s i t e of a c t i o n . W h e r e a s m o s t " t r a d i t i o n a l " f o r m u l a t i o n s h a v e t o b e e i t h e r i n j e c t e d or i n g e s t e d , p o l y m e r i c c o n t r o l l e d r e l e a s e s y s t e m s c a n be p l a c e d i n t o v i r t u a l l y a n y one of the a v a i l a b l e b o d y c a v i t i e s , c a n b e i m p l a n t e d , o r c a n b e a t t a c h e d e x t e r n a l l y to t h e s k i n . T h u s a w i d e c h o i c e of n e w r o u t e s o f d r u g a d m i n i s t r a t i o n h a s b e c o m e available. N o s e d r o p s , eye d r o p s , l o z e n g e s , a n d s k i n o i n t m e n t s h a v e b e e n a v a i l a b l e for d e c a d e s , h o w e v e r , t h e s e f o r m u l a t i o n s h a v e b e e n l i m i t e d i n t h e p a s t to t h e l o c a l a d m i n i s t r a t i o n of d r u g s i n t e n d e d to a c t i n t h e n o s e , eye, m o u t h / t h r o a t , o r s k i n r e s p e c t i v e l y . In recent years, a n u m b e r of a c a d e m i c a n d i n d u s t r i a l laboratories have investigated the systemic a d m i n i s t r a t i o n of d r u g s v i a the n a s a l m e m b r a n e s ( n a s a l r o u t e ) , t h e m u c o u s m e m b r a n e s of t h e m o u t h ( b u c c a l r o u t e ) , t h e eye ( o p h t h a l m i c route), or the s k i n ( t r a n s d e r m a l delivery). T h e s e r o u t e s h a v e b e e n e x p l o r e d i n p a r t i c u l a r for p e p t i d e d r u g s ( s u c h a s i n s u l i n ) w h i c h c a n n o t c u r r e n t l y be a d m i n i s t e r e d orally. In this context, t r a n s d e r m a l delivery a n d b u c c a l delivery have been recognized as p a r t i c u l a r l y p r o m i s i n g a n d are widely investigated.


2.

SINKO AND K O H N



Materials & Polymer Science

Physical Chemistry

F i g u r e 1: S c i e n t i f i c d i s c i p l i n e s t h a t relate to d r u g delivery. Often, advances m a d e i n the peripheral disciplines c o n t r i b u t e d s i g n i f i c a n t l y to a d v a n c e s m a d e i n d r u g delivery. A particularly strong relationship exists between polymer chemistry a n d d r u g delivery, since m o s t d r u g delivery systems depend o n polymeric materials.

Toxic Level

Time

F i g u r e 2: T h e o r e t i c a l p l a s m a c o n c e n t r a t i o n s a f t e r a d m i n i s t r a t i o n of v a r i o u s dosage f o r m s : (a) S t a n d a r d o r a l d o s e ; (b) O r a l o v e r d o s e ; (c) I.V. i n j e c t i o n ; a n d (d) C o n t r o l l e d r e l e a s e s y s t e m .


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Transdermal Delivery Systems. T r a n s d e r m a l delivery, where a c o n t r o l l e d release s y s t e m i s a t t a c h e d e x t e r n a l l y to t h e s k i n , h a s e m e r g e d as the c o m m e r c i a l l y m o s t s u c c e s s f u l n e w r o u t e of d r u g a d m i n i s t r a t i o n . Several t r a n s d e r m a l delivery systems are already o n t h e m a r k e t (Table I). The commercial products listed i n Table I were made possible i n p a r t b y a d v a n c e s i n the d e s i g n a n d f a b r i c a t i o n of p o l y m e r i c m e m b r a n e s a n d f i l m s . T h e u s e of a d v a n c e d p o l y m e r technologies i n t h e f o r m u l a t i o n of t r a n s d e r m a l d r u g delivery s y s t e m s p r o v i d e s t h u s a g o o d i l l u s t r a t i o n for t h e d e p e n d e n c y of p r o g r e s s i n d r u g d e l i v e r y o n progress i n the material sciences.

T a b l e I:

Commercially Available T r a n s d e r m a l D r u g Delivery Systems

Trade

Name

D r u g Delivered

System Type

Transderm-Scop

Scopolamine

Reservoir with R L M

Duragesic Transdermal System

Fentanyl

Reservoir w i t h R L M

1

Catapres TTS

Clonidine

Reservoir with R L M

1

Estraderm

Estradiol


1

Transderm-Nitro

Nitroglycerine


1

N i t r o - D u r II

Nitroglycerine

Matrix dispersion i n adhesive polymer

Nitro-Dur

Nitroglycerine

Matrix dispersion

Nitrodisc

Nitroglycerine

Hybrid reservoir a n d matrix dispersion

Habitrol

Nicotine

Matrix with adhesive layer

Nicotrol

Nicotine

D i s p e r s i o n of m a t r i x and drug

Prostep

Nicotine

Matrix dispersion

1

1

R L M : Rate Limiting Membrane

C o m m o n l y r e c o g n i z e d a d v a n t a g e s of t r a n s d e r m a l d r u g d e l i v e r y a r e t h e a b i l i t y to i n t e r r u p t t h e f l o w of d r u g b y s i m p l y r e m o v i n g t h e t r a n s d e r m a l p a t c h f r o m t h e s k i n a n d t h e c i r c u m v e n t i o n of f i r s t - p a s s m e t a b o l i s m i n t h e l i v e r - o n e o f t h e m o s t i m p o r t a n t d i s a d v a n t a g e s of





the o r a l route of d r u g a d m i n i s t r a t i o n . T r a n s d e r m a l systems c o n s i s t u s u a l l y of a d r u g reservoir, a diffusion-limiting m e m b r a n e , a n d a n a d h e s i v e l a y e r for a t t a c h m e n t to t h e s k i n . P e n e t r a t i o n e n h a n c e r s a r e o f t e n a d d e d to t h e f o r m u l a t i o n to i n c r e a s e t h e r a t e o f d r u g d i f f u s i o n t h r o u g h t h e s k i n . A m a j o r l i m i t a t i o n of t r a n s d e r m a l s y s t e m s i s t h a t o n l y m i n u t e q u a n t i t i e s of d r u g c a n be a d m i n i s t e r e d i n t h i s w a y s i n c e t h e rate of d r u g d i f f u s i o n t h r o u g h i n t a c t s k i n is g e n e r a l l y low. T h e r e f o r e , t r a n s d e r m a l s y s t e m s a r e a p p l i c a b l e o n l y for h i g h l y p o t e n t drugs. A f u r t h e r l i m i t a t i o n r e l a t e s to t h e o b s e r v a t i o n t h a t s o m e d e g r e e of s k i n i r r i t a t i o n c a n a p p a r e n t l y n o t b e a v o i d e d w h e n t h e s k i n i s e x p o s e d to r e l a t i v e l y h i g h l o c a l c o n c e n t r a t i o n s of d r u g a n d / o r v a r i o u s p e n e t r a t i o n e n h a n c e r s , a n d i s c o v e r e d for p r o l o n g e d p e r i o d s by the transdermal patch. Buccal Delivery. I n a d d i t i o n to t r a n s d e r m a l d e l i v e r y , b u c c a l delivery is n o w recognized as p a r t i c u l a r l y p r o m i s i n g a n d is widely investigated i n i n d u s t r y . Interestingly, academic laboratories have so f a r s h o w n l e s s i n t e r e s t i n t h i s r e s e a r c h effort. B u c c a l d e l i v e r y offers e x c e l l e n t a c c e s s i b i l i t y so t h a t d r u g d e l i v e r y s y s t e m s c a n b e e a s i l y attached a n d removed. D r u g s absorbed by the b u c c a l route w i l l avoid f i r s t p a s s h e p a t i c m e t a b o l i s m , a n a d v a n t a g e for t h e d e l i v e r y o f peptides and small proteins. B u c c a l d r u g delivery devices are effective b e c a u s e t h e y i n c r e a s e t h e r e t e n t i o n t i m e i n t h e o r a l m u c o s a by a bioadhesion mechanism. B u c c a l d r u g d e l i v e r y h a s b e e n u s e d for b o t h l o c a l a n d s y s t e m i c a d m i n i s t r a t i o n of d r u g s . T h e c h a l l e n g e of c o n t r o l l e d b u c c a l d r u g d e l i v e r y i s to d e v e l o p s y s t e m s t h a t i n c r e a s e b u c c a l r e s i d e n c e t i m e b y m u c o s a l adhesion. M u c o s a l adhesion is achieved u s i n g a polymer or c o m b i n a t i o n of p o l y m e r s s u c h as h y d r o x y p r o p y l c e l l u l o s e , e t h y l c e l l u lose, polymethylmethacrylate a n d s o d i u m polyacrylate that exhibit adhesive properties when i n contact with saliva. The three c o m m o n l y u s e d d e l i v e r y s y s t e m s i n c l u d e a d h e s i v e t a b l e t s (12), a d h e s i v e g e l s (13) a n d a d h e s i v e p a t c h e s (14). A n e x a m p l e of a c o m m e r c i a l b u c c a l tablet is S u s a d r i n . S u s a d r i n delivers nitroglycerine i n t h e t r e a t m e n t of a n g i n a p e c t o r i s for 5 h c o m p a r e d to a b o u t 5 m i n for c o n v e n t i o n a l s u b l i n g u a l t a b l e t s (15). S u s a d r i n uses a n adhesive c o m p r i s e d o f h y d r o x y p r o p y l c e l l u l o s e a n d e t h y l c e l l u l o s e (12). C l a s s i f i c a t i o n o f D r u g Release S y s t e m s . A c o m m o n l y u s e d c l a s s i f i c a t i o n s c h e m e i s b a s e d o n t h e p h y s i c a l d e s i g n of t h e d r u g r e l e a s e d e v i c e a n d l e a d s to t h e d i f f e r e n t i a t i o n b e t w e e n t w o f u n d a m e n t a l l y d i f f e r e n t t y p e s o f d e v i c e s , t h e matrix system a n d the reservoir system (16). A m a t r i x s y s t e m c o n s i s t s of a d r u g u n i f o r m l y d i s p e r s e d w i t h i n a p o l y m e r , w h i l e a r e s e r v o i r s y s t e m c o n s i s t s of a s e p a r a t e d r u g p h a s e (e.g., d r u g p a r t i c l e s o r d r o p l e t s ) p h y s i c a l l y d i s p e r s e d w i t h i n a surrounding, rate-limiting polymeric phase. B o t h matrix systems a n d reservoir s y s t e m s c a n be formulated i n a wide range of s h a p e s a n d s i z e s r a n g i n g f r o m m i c r o p a r t i c l e s to l a r g e d i s k s o r s l a b s . Occasionally, additional device-based classifications are u s e d . F o r example, controlled release devices m a y be further classified as


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h y d r o g e l s , t r a n s d e r m a l s y s t e m s , o s m o t i c s y s t e m s etc. Those c l a s s i f i c a t i o n s , h o w e v e r , t e n d to b e l e s s u s e f u l t h a n t h e f u n d a m e n t a l differentiation between matrix systems a n d reservoir systems. T h r e e different m e c h a n i s m s of d r u g release c a n be identified a n d c a n b e r e f e r r e d to a s " s o l v e n t c o n t r o l l e d " , " d i f f u s i o n c o n t r o l l e d " , a n d " c h e m i c a l l y controlled" release. These classifications represent theor e t i c a l s i t u a t i o n s w h e r e t h e r a t e of d r u g r e l e a s e i s c o n t r o l l e d p r e d o m i n a n t l y b y s o l v e n t i n t e r a c t i o n s s u c h a s s w e l l i n g of t h e p o l y m e r , b y t h e d i f f u s i o n of d r u g t h r o u g h a p o l y m e r i c m a t r i x or a m e m b r a n e , or b y c h e m i c a l p r o c e s s e s s u c h as p o l y m e r d e g r a d a t i o n , e r o s i o n , or the cleavage of a d r u g f r o m a p o l y m e r i c carrier. Obviously, in many p r a c t i c a l d e v i c e s , t h e r a t e of d r u g r e l e a s e m a y b e affected b y v a r i o u s c o m b i n a t i o n s of the above m e c h a n i s m s . T h e s e m e c h a n i s m s are also b e i n g u s e d a s a b a s i s for t h e c l a s s i f i c a t i o n of t h e r e l e a s e d e v i c e s themselves a n d t h u s one m a y d i s t i n g u i s h between solvent controlled, diffusion controlled or c h e m i c a l l y controlled systems. Solvent Controlled Systems. T h e two p r i m a r y s o l v e n t - c o n t r o l l e d m e c h a n i s m s of d r u g release i n c l u d e p o l y m e r s w e l l i n g a n d o s m o s i s . M o s t s w e l l i n g c o n t r o l l e d s y s t e m s a r e h y d r o g e l s , e.g., w a t e r s o l u b l e polymers that have been rendered insoluble by crosslinking. In these s y s t e m s , the rate of s w e l l i n g (and t h u s the rate of d r u g release) d e p e n d s o n the h y d r o p h i l i c / h y d r o p h o b i c b a l a n c e of t h e p o l y m e r i c m a t r i x a n d t h e d e g r e e of c r o s s l i n k i n g (17). For example, Korsmeyer a n d P e p p a s ( 1 8 ) i n v e s t i g a t e d t h e r e l e a s e of t h e o p h y l l i n e f r o m h y d r o g e l s m a d e of h i g h l y c r o s s l i n k e d poly (vinyl alcohol). Other e x a m p l e s o f s w e l l a b l e s y s t e m s w e r e r e p o r t e d b y C o n t e et a l . (19) w h o u s e d d i c l o f e n a c s o d i u m a n d c i m e t i d i n e to i n v e s t i g a t e t h e m e c h a n i s m of d r u g release f r o m dosage forms b a s e d o n p o l y v i n y l alcohol), hydroxypropylmethylcellulose, a n d carboxymethylcellulose. In these systems, release w a s controlled b y the s i m u l t a n e o u s s w e l l i n g a n d e r o s i o n o f t h e p o l y m e r i c m a t r i x . B r o n d s t e d a n d K o p e c e k (17) h a v e r e p o r t e d t h e u s e of p H s e n s i t i v e h y d r o g e l s t h a t s w e l l i n t h e distal intestine and colon. Once swelling begins, the c r o s s l i n k s b e c o m e a c c e s s i b l e to s p e c i f i c c o l o n i c e n z y m e s (azoreductases) l e a d i n g to t h e d e g r a d a t i o n of t h e h y d r o g e l a n d t h e c o n c o m i t a n t r e l e a s e o f d r u g i n t o t h e c o l o n . T h i s i s a n e x a m p l e for t h e u s e o f b o t h solvent control a n d chemical control w i t h i n the same system. O s m o s i s r e p r e s e n t s t h e s e c o n d m e c h a n i s m of s o l v e n t c o n t r o l . O s m o t i c s y s t e m s a r e u s u a l l y c o m p o s e d of a d r u g r e s e r v o i r e n c l o s e d b y a water-selective polymeric membrane. T h e m e m b r a n e a l l o w s for t r a n s p o r t o f w a t e r b u t d o e s n o t a l l o w for t h e p a s s a g e o f d r u g . T h e polymeric m e m b r a n e has a s m a l l opening t h r o u g h w h i c h d r u g is r e l e a s e d a s a r e s u l t o f t h e b u i l t - u p of h y d r o s t a t i c p r e s s u r e w i t h i n t h e device. A n e x a m p l e of t h i s technology is the i m p l a n t a b l e A l z e t m i n i p u m p a n d t h e o r a l v e r s i o n , O s m e t , for c o n t r o l l e d o r a l d r u g delivery. T h e widely k n o w n O r o s tablet s y s t e m is a n e x t e n s i o n of the O s m e t t e c h n o l o g y . A n e x a m p l e o f t h e c o m m e r c i a l s u c c e s s of o s m o t i c delivery systems is Procardia X L . P r o c a r d i a X L is a once-a-day


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p r o d u c t u s i n g the Oros technology. Commercially, the system is i n t e n d e d to p r o l o n g t h e n i f e d i p i n e p r o d u c t l i n e . O n e o f t h e a d v a n t a g e s of t h i s s y s t e m is t h a t the dosage frequency c o u l d be r e d u c e d f r o m t h r e e t i m e s d a i l y for t h e t r a d i t i o n a l d o s a g e f o r m to o n c e d a i l y . Diffusion Controlled Systems. Reservoir a n d m a t r i x s y s t e m s rep r e s e n t f u n d a m e n t a l l y d i f f e r e n t s y s t e m d e s i g n s for t h e d i f f u s i o n c o n t r o l l e d release of d r u g s . A s defined above, a t y p i c a l reservoir s y s t e m c o n s i s t s of a n o n d e g r a d a b l e , rate-limiting polymeric m e m b r a n e , s e p a r a t i n g a c o r e of d r u g f r o m t h e b i o l o g i c a l e n v i r o n m e n t . Typically, reservoir systems have been formulated as capsules, m i c r o c a p s u l e s , h o l l o w f i b e r s , o r t u b e s w i t h s e a l e d e n d s ( F i g u r e 3). S e v e r a l nondegradable polymers w i t h F D A approval history (such as polys i l o x a n e s u s e d i n the f o r m u l a t i o n of the N o r p l a n t system) are a v a i l a b l e . I n r e s e r v o i r s y s t e m s c o n s i s t i n g of n o n d e g r a d a b l e p o l y m e r s , t h e rate of d r u g release is s t r i c t l y c o n t r o l l e d b y the rate of d r u g d i f f u s i o n t h r o u g h the p o l y m e r i c m e m b r a n e . T h u s , the f o r m u l a t i o n of t h e d r u g c o r e a n d t h e f a b r i c a t i o n of f u n c t i o n a l s y s t e m s a r e r e l a t i v e l y simple tasks. T w o different types of c o n t r o l l i n g m e m b r a n e s , h o m o g e n e o u s or m i c r o p o r o u s , are b e i n g u s e d i n the f o r m u l a t i o n of reservoir s y s t e m s . M i c r o p o r o u s m e m b r a n e s have the advantage that d r u g diffuses t h r o u g h pores t h a t are filled w i t h the s a m e m e d i u m as the reservoir. Diffusion control i n homogeneous membranes, on the other h a n d , depends o n m e m b r a n e - d r u g partitioning. T r a n s d e r m a l d r u g delivery s y s t e m s u t i l i z e b o t h of t h e s e m e c h a n i s m s (Table I). F o r e x a m p l e , t h e Transderm-Nitro system uses a homogeneous EVA copolymer m e m b r a n e while the T r a n s d e r m - S c o p s y s t e m is based o n a m i c r o p o r o u s r a t e - c o n t r o l l i n g p o l y p r o p y l e n e m e m b r a n e (20). O n e of t h e p o t e n t i a l d i s a d v a n t a g e s of i m p l a n t a b l e r e s e r v o i r s y s t e m s ( s u c h a s t h e N o r p l a n t c o n t r a c e p t i v e device) i s t h e d a n g e r o f "dose d u m p i n g " . If t h e s u r r o u n d i n g p o l y m e r i c m e m b r a n e s h o u l d b e c o m e l e a k y d u e to c r a c k s o r s u d d e n r u p t u r e , t h e e n t i r e d r u g c o r e c o u l d be released into c i r c u l a t i o n w i t h i n a very s h o r t time. T h e r e f o r e , s p e c i a l c o n s i d e r a t i o n h a s to b e g i v e n to t h e u s e of d e g r a d a b l e p o l y m e r s i n t h e d e s i g n of r e s e r v o i r s y s t e m s . Here, the n e e d to k e e p t h e p o l y m e r i c m e m b r a n e m e c h a n i c a l l y i n t a c t t h r o u g h o u t the p e r i o d of d r u g release r e q u i r e s a very c a r e f u l o p t i m i z a t i o n of t h e p o l y m e r p r o p e r t i e s so t h a t the p r o c e s s of d r u g release i s essentially completed by the time the polymeric m e m b r a n e looses its m e c h a n i c a l s t r e n g t h d u e to d e g r a d a t i o n . A s a r u l e of t h u m b , o n e c a n e x p e c t t h a t t h e f o r m u l a t i o n of a d e v i c e w i t h a n a c t i v e r e l e a s e t i m e o f X will require a polymer whose complete bioabsorption from the i m p l a n t s i t e w i l l o c c u r o v e r a p e r i o d of 3 X . A s a c o n s e q u e n c e , u p o n repeated a d m i n i s t r a t i o n of the device, a "steady-state" n u m b e r of active a n d p a r t i a l l y degraded, empty " s h e l l s " w i t h i n the b o d y of the p a t i e n t i s e s t a b l i s h e d . P o l y c a p r o l a c t o n e , for e x a m p l e , h a s b e e n u s e d i n t h e f o r m u l a t i o n of a reservoir-type i m p l a n t a b l e c o n t r a c e p t i v e d e v i c e (the C a p r o n o r s y s t e m ) t h a t i s b e i n g t e s t e d c l i n i c a l l y i n p h a s e II t r i a l s i n m a n y c o u n t r i e s (21). In t h a t s y s t e m , d r u g release is


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diffusion controlled over a period of a b o u t o n e year, w i t h t h e p o l y c a p r o l a c t o n e m e m b r a n e completely d e g r a d i n g after a b o u t 3 y e a r s f r o m t h e date of i m p l a n t a t i o n . T h u s , u p o n long-term, repeated u s e of the device, o n e active a n d two "empty" devices w o u l d a c c u m u l a t e i n the patient. Whether the Capronor system h a s significant advantages over the Norplant system (a n o n d e g r a d a b l e reservoir-type contraceptive b a s e d o n a polysiloxane membrane) depends to a large extend o n t h e c i r c u m s t a n c e s of the patient, the ease at w h i c h t h e nondegradable system c a n be removed, a n d the general medical environment. In developing countries where trained surgeons m a y n o t b e available for i m p l a n t r e m o v a l o r w h e r e p a t i e n t s m a y n o t r e t u r n to t h e c l i n i c to h a v e t h e i r i m p l a n t removed, t h e d e g r a d a b l e s y s t e m m a y indeed be t h e preferred s y s t e m configuration. A l t h o u g h short-duration reservoir systems c a n be formulated w i t h fast-degrading polymeric membranes, as a general rule, slowly d e g r a d i n g p o l y m e r s a p p e a r to b e p a r t i c u l a r l y u s e f u l for t h e d e s i g n of degradable reservoir systems. Fortunately, several s u c h polymers with promising tissue compatibility a n d suitable physicomechanical p r o p e r t i e s a r e c o m m e r c i a l l y a v a i l a b l e (Table II). T a b l e II: S o m e S l o w - D e g r a d i n g P o l y m e r s t h a t c a n b e C o n s i d e r e d for the Design of Long-Acting, Degradable Reservoir Systems Polymer Poly(lactic

C o m m e n t s a n d References acid)

Polycaprolactone

H i g h molecular weight preparations preferred, medical grades readily available from commercial suppliers (e.g., M e d i s o r b ) (22). Readily available from commercial s u p p l i e r s (e.g., P o l y s c i e n c e s ) (21).

P o l y h y d r o x y b u t y r a t e a n d co- P r e p a r e d b y b i o s y n t h e s i s , different polymers w i t h valeric acid grades w i t h valeric acid contents from a b o u t 7 to 3 0 % a r e a v a i l a b l e f r o m I C I u n d e r t h e t r a d e n a m e B i o p o l [23,24). Poly(N-palmitoyl-trans-4h y d r o x y - L - p r o l i n e ester)

An amino acid derived polyester, b e l o n g i n g to a n e w c l a s s of p o t e n t i a l implant materials, the pseudo-poly (amino acids). Available from S i g m a C h e m i c a l C o m p a n y (25,26).

Poly(DTH

A polycarbonate made of derivatives of the n a t u r a l a m i n o acid L-tyrosine. A v a i l able from S i g m a C h e m i c a l C o m p a n y (16,27-29).

carbonate)



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In a m a t r i x system, the d r u g is uniformly distributed w i t h i n the polymeric phase. Like reservoir systems, m a t r i x systems c a n be f a b r i c a t e d i n a v a r i e t y of s h a p e s , i n c l u d i n g m i c r o s p h e r e s t h a t w o u l d b e s u i t a b l e for i n j e c t i o n . M a t r i x s y s t e m s are safer t h a n reservoir systems, since no potentially lethal "drug spill" c a n occur even if the device w o u l d break into several pieces. If t h e m a t r i x s y s t e m i s fabricated f r o m a degradable polymer, the release m e c h a n i s m is often a c o m b i n a t i o n of d i f f u s i o n a l release a n d c h e m i c a l l y c o n t r o l l e d release. T h i s case will be d i s c u s s e d i n more detail i n the the section o n chemically controlled systems. A s d r u g is being released from a nondegradable m a t r i x system, t h e r a t e of d i f f u s i o n t e n d s to d e c r e a s e . F o r this reason, it c a n be q u i t e d i f f i c u l t to f o r m u l a t e m a t r i x s y s t e m s t h a t w i l l e x h i b i t c o n s t a n t d r u g r e l e a s e r a t e s i n a r e p r o d u c i b l e f a s h i o n o v e r e x t e n d e d p e r i o d s of t i m e (30). A p o s s i b l e s o l u t i o n to t h i s i n t r i n s i c p r o b l e m w a s s u g g e s t e d b y L a n g e r et a l . w h o u s e d m a t r i x s y s t e m s w i t h s p e c i a l g e o m e t r i e s (coated h e m i s p h e r i c devices) to c o m p e n s a t e for t h e d e c r e a s e i n t h e r a t e o f d i f f u s i o n w i t h t i m e (30). In spite of t h e s e difficulties, the m a t r i x system is a widely studied s y s t e m design that i s s u i t a b l e for v a r i o u s d r u g r e l e a s e a p p l i c a t i o n s . F o r e x a m p l e , t h e p o l y a n h y d r i d e b a s e d r e l e a s e s y s t e m for B C N U ( c u r r e n t l y i n p h a s e 3 c l i n i c a l trials) is a m a t r i x s y s t e m (31). Likewise, among the t r a n s d e r m a l s y s t e m s , N i t r o - D u r a n d N i t r o - D u r 11 a r e b a s e d o n a nondegradable matrix design. Chemically Controlled Systems. S y s t e m s i n w h i c h the rate of d r u g r e l e a s e is p r e d o m i n a n t l y c o n t r o l l e d b y t h e r a t e of polymer d e g r a d a t i o n , the rate of the p h y s i c a l e r o s i o n of the p o l y m e r , or the rate at w h i c h a d r u g is cleaved f r o m the p o l y m e r b a c k b o n e are considered chemically controlled release systems. T h e two m a i n types of c h e m i c a l l y controlled s y s t e m s are m a t r i x s y s t e m s b a s e d o n d e g r a d a b l e p o l y m e r s a n d p e n d e n t c h a i n s y s t e m s ( F i g u r e 4). W i t h i n t h e c o n t e x t of t h i s c h a p t e r , w e l i m i t o u r d i s c u s s i o n to t h e case of a s o l i d , p o l y m e r i c m a t r i x - t y p e release s y s t e m . The transf o r m a t i o n of s u c h a n i m p l a n t into water s o l u b l e material(s) is best described b y the t e r m "bioerosion". T h i s process is associated w i t h m a c r o s c o p i c c h a n g e s i n the a p p e a r a n c e of the device, c h a n g e s i n the p h y s i c o m e c h a n i c a l p r o p e r t i e s of t h e p o l y m e r i c m a t e r i a l , p h y s i c a l processes s u c h as swelling, deformation or s t r u c t u r a l disintegration, w e i g h t l o s s , a n d t h e e v e n t u a l l o s s of f u n c t i o n . A l l of t h e s e p h e n o m e n a r e p r e s e n t d i s t i n c t a n d often i n t e r c o n n e c t e d a s p e c t s o f t h e c o m p l e x b i o e r o s i o n b e h a v i o r of a d e g r a d a b l e m a t r i x device. It i s i m p o r t a n t to n o t e t h a t t h e b i o e r o s i o n o f a s o l i d d e v i c e i s n o t n e c e s s a r i l y d u e to t h e c h e m i c a l c l e a v a g e of t h e p o l y m e r b a c k b o n e , or t h e c h e m i c a l cleavage of c r o s s l i n k s or s i d e c h a i n s . R a t h e r , s i m p l e s o l u b i l i z a t i o n of t h e i n t a c t p o l y m e r , for i n s t a n c e , d u e t o c h a n g e s i n p H , m a y a l s o l e a d to t h e e r o s i o n of a s o l i d d e v i c e . T w o d i s t i n c t m o d e s of b i o e r o s i o n h a v e b e e n d e s c r i b e d i n t h e l i t e r a t u r e (32). I n " b u l k e r o s i o n " , t h e r a t e of w a t e r p e n e t r a t i o n i n t o the s o l i d device exceeds the rate at w h i c h the p o l y m e r is



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Figure 3: S c h e m a t i c r e p r e s e n t a t i o n s of a t y p i c a l r e s e r v o i r s y s t e m : (A) C r o s s - s e c t i o n a l v i e w s h o w i n g d r u g p a r t i c l e s ( b l a c k ) dispersed w i t h i n the d r u g core; (B) Reservoir system f o r m u l a t e d i n t h e s h a p e o f a t u b e . T h e d r u g c o r e i s filled i n t o t h e t u b e w h o s e e n d s are t h e n sealed. D r u g release i s c o n t r o l l e d b y t h e d i f f u s i o n of the d r u g t h r o u g h the s u r r o u n d i n g , ratelimiting polymeric membrane.

F i g u r e 4: S c h e m a t i c r e p r e s e n t a t i o n of a " p e n d e n t chain s y s t e m " , u s e d p r e d o m i n a n t l y i n the d e s i g n of soluble, m a c r o m o l e c u l a r d r u g conjugates. V a r i o u s modifications of t h i s figure h a v e b e e n p u b l i s h e d i n a l a r g e n u m b e r p a p e r s t o i l l u s t r a t e the c o n c e p t of a p e n d e n t c h a i n s y s t e m . S u c h a s y s t e m c o n s i s t s u s u a l l y of a d e g r a d a b l e or n o n d e g r a d a b l e p o l y m e r i c b a c k b o n e to w h i c h a p h a r m a c o l o g i c a l l y active agent is covalently attached t h r o u g h reactive pendent c h a i n s . A spacer m a y be placed between the d r u g a n d the polymer b a c k b o n e . Targeting moieties (such as m o n o c l o n a l antibodies) a n d solubilizing elements (such as polyethylene glycol units) can be i n c o r p o r a t e d i n t o t h e s y s t e m d e s i g n to i m p r o v e t h e o v e r a l l p e r f o r m a n c e of the d r u g carrier. N u m e r o u s p o l y m e r s s u c h as dextran, polylysine, poly(glutamic acid), or f u n c t i o n a l i z e d d e r i v a t i v e s of p o l y a c r y l a m i d e h a v e b e e n u s e d as b a c k b o n e s .


2.

SINKO AND K O H N



t r a n s f o r m e d into water soluble material(s). C o n s e q u e n t l y , the u p t a k e of water is followed b y a n erosion process that o c c u r s t h r o u g h o u t the e n t i r e v o l u m e of t h e s o l i d d e v i c e . D u e to t h e r a p i d p e n e t r a t i o n o f w a t e r into the m a t r i x of h y d r o p h i l i c p o l y m e r s , m o s t of the c u r r e n t l y a v a i l a b l e p o l y m e r s w i l l g i v e rise to b u l k e r o d i n g d e v i c e s . I n a t y p i c a l " b u l k erosion" process, c r a c k s a n d crevices will f o r m t h r o u g h o u t the d e v i c e w h i c h m a y r a p i d l y c r u m b l e i n t o p i e c e s . A g o o d i l l u s t r a t i o n for a t y p i c a l b u l k e r o s i o n p r o c e s s is the d i s i n t e g r a t i o n of a s u g a r c u b e that h a s been placed into water. D e p e n d i n g o n the specific a p p l i c a t i o n , t h e o f t e n u n c o n t r o l l a b l e t e n d e n c y o f b u l k e r o d i n g d e v i c e s to c r u m b l e i n t o l i t t l e p i e c e s c a n b e a d i s a d v a n t a g e . It i s e a s y to see t h a t t h e rate of d r u g release c a n n o t be a d e q u a t e l y c o n t r o l l e d w h i l e t h e release device disintegrates into r a n d o m fragments. A l t e r n a t i v e l y , i n " s u r f a c e e r o s i o n " t h e rate at w h i c h w a t e r p e n e t r a t e s i n t o t h e p o l y m e r i c d e v i c e i s s l o w e r t h a n t h e r a t e of t r a n s f o r m a t i o n of the p o l y m e r into water soluble material(s). In this case, the t r a n s f o r m a t i o n of t h e p o l y m e r i n t o w a t e r s o l u b l e m a t e r i a l ( s ) i s l i m i t e d to t h e o u t e r s u r f a c e of the s o l i d device. The device will therefore become t h i n n e r w i t h time, while m a i n t a i n i n g its s t r u c t u r a l integrity t h r o u g h o u t m u c h of t h e e r o s i o n p r o c e s s . I n o r d e r to o b s e r v e s u r f a c e e r o s i o n , t h e p o l y m e r m u s t b e h y d r o p h o b i c e n o u g h to i m p e d e t h e r a p i d i m b i b i t i o n of w a t e r i n t o t h e i n t e r i o r o f t h e d e v i c e . I n a d d i t i o n , t h e rate at w h i c h the p o l y m e r is t r a n s f o r m e d i n t o w a t e r s o l u b l e m a t e r i a l ( s ) h a s to be r e a s o n a b l y fast. Under these conditions, s c a n n i n g electron m i c r o s c o p i c e v a l u a t i o n of surface e r o d i n g devices h a s sometimes s h o w n a s h a r p border between the eroding surface l a y e r a n d t h e i n t a c t p o l y m e r i n t h e c o r e of t h e d e v i c e (33). S o far, t r u e s u r f a c e e r o s i o n h a s b e e n o b s e r v e d o n l y i n a s m a l l n u m b e r of polymers. C u r r e n t l y , p o l y a n h y d r i d e s [34-37) a n d p o l y ( o r t h o e s t e r s ) (38-41) are the best k n o w n e x a m p l e s of p o l y m e r s t h a t c a n be fabricated into surface eroding devices. W h i l e i n t h e o r y s u r f a c e e r o d i n g m a t r i x s y s t e m s a p p e a r to be preferable over b u l k eroding systems, i d e a l surface e r o s i o n c a n only be achieved i n " u n l o a d e d " devices or w h e n h y d r o p h o b i c d r u g s are incorporated into the polymer matrix. In practice, hydrophilic drugs ( t h a t t e n d to c a u s e t h e i m b i b i t i o n of w a t e r i n t o t h e d e v i c e ) t e n d to l e a d to c o m p l e x d r u g r e l e a s e p r o f i l e s t h a t a r e o n l y p a r t i a l l y c o n t r o l l e d b y polymer erosion. O n the other h a n d , by formulating b u l k eroding m a t r i x systems i n s u c h a way that m o s t d r u g is released before the device physically disintegrates, b u l k eroding m a t r i x systems c a n prov i d e c o n s t a n t d r u g r e l e a s e r a t e s . C o n t r a r y to a w i d e l y h e l d m i s c o n c e p t i o n , s u r f a c e e r o s i o n i s t h e r e f o r e n o t a n e c e s s a r y r e q u i r e m e n t for t h e f o r m u l a t i o n of degradable m a t r i x s y s t e m s t h a t s h o w c o n s t a n t release. F a c t o r s I n f l u e n c i n g the D e g r a d a t i o n of a P o l y m e r i c D e v i c e . I n o r d e r to s u c c e s s f u l l y d e s i g n c h e m i c a l l y c o n t r o l l e d d r u g r e l e a s e s y s t e m s , it is n e c e s s a r y to u n d e r s t a n d t h e m a i n f a c t o r s t h a t d e t e r m i n e the o v e r a l l rate of the e r o s i o n p r o c e s s . In the case of a


29


30


solid m a t r i x s y s t e m , the m a i n parameters are the c h e m i c a l stability of t h e p o l y m e r b a c k b o n e , the h y d r o p h o b i c i t y of the p o l y m e r i c m a t r i x , the m o r p h o l o g y of the polymer, the i n i t i a l m o l e c u l a r weight of the p o l y m e r , the degree of s w e l l i n g of the d r u g - l o a d e d p o l y m e r i c m a t r i x , the f a b r i c a t i o n process, the presence of c a t a l y s t s , additives or plasticizers, a n d the geometry of the i m p l a n t e d device. T h e s u s c e p t i b i l i t y of the p o l y m e r i c b a c k b o n e t o w a r d h y d r o l y t i c cleavage is probably the most f u n d a m e n t a l parameter. Generally s p e a k i n g , a n h y d r i d e s t e n d to h y d r o l y z e f a s t e r t h a n e s t e r b o n d s w h i c h i n t u r n hydrolyze faster t h a n a m i d e b o n d s . T h u s , p o l y a n h y d r i d e s w i l l t e n d to d e g r a d e faster t h a n polyesters w h i c h i n t u r n w i l l h a v e a h i g h e r t e n d e n c y to b i o e r o d e t h a n p o l y a m i d e s . H o w e v e r , s o l e l y b a s e d o n t h e k n o w n s u s c e p t i b i l i t y of the p o l y m e r b a c k b o n e s t r u c t u r e t o w a r d h y d r o l y s i s i t i s n o t p o s s i b l e to p r e d i c t t h e r a t e a t w h i c h a n y given p o l y m e r i c device w i l l u n d e r g o bioerosion. T h e o b s e r v e d e r o s i o n r a t e of a d r u g - l o a d e d m a t r i x s y s t e m i s s t r o n g l y d e p e n d a n t o n t h e a b i l i t y of w a t e r m o l e c u l e s to p e n e t r a t e i n t o t h e p o l y m e r i c m a t r i x . T h e h y d r o p h o b i c i t y of t h e p o l y m e r w h i c h i s a f u n c t i o n o f t h e s t r u c t u r e of t h e m o n o m e r i c s t a r t i n g m a t e r i a l s a s w e l l a s the n a t u r e a n d l o a d i n g of the d r u g c a n therefore h a v e a n overw h e l m i n g influence o n the observed bioerosion rate. For instance, t h e e r o s i o n rate of p o l y a n h y d r i d e s c a n be s l o w e d b y a b o u t three orders of m a g n i t u d e w h e n the h y d r o p h i l i c sebacic a c i d is replaced b y h y d r o p h o b i c bis(carboxy phenoxy)propane as the m o n o m e r i c starting m a t e r i a l (37). L i k e w i s e , devices m a d e of poly(glycolic acid) e r o d e faster t h a n i d e n t i c a l devices m a d e of the m o r e h y d r o p h o b i c p o l y (lactic acid), a l t h o u g h the ester b o n d s have a b o u t the s a m e c h e m i c a l reactivity toward water i n both polymers. T h e observed bioerosion rate is further i n f l u e n c e d b y the m o r p h o l o g y of the p o l y m e r . W i t h i n the f r a m e w o r k of t h i s d i s c u s s i o n , three distinct morphological states (semicrystalline, a m o r p h o u s g l a s s y , a n d a m o r p h o u s - r u b b e r y ) h a v e to b e c o n s i d e r e d . In a semicrystalline polymer, the crystalline regions are m o s t d e n s e l y p a c k e d a n d offer t h e h i g h e s t r e s i s t a n c e to t h e p e n e t r a t i o n o f water. C o n s e q u e n t l y , t h e r a t e o f b a c k b o n e h y d r o l y s i s t e n d s to b e h i g h e r i n the a m o r p h o u s regions of a s e m i c r y s t a l l i n e p o l y m e r t h a n i n the crystalline regions. A good i l l u s t r a t i o n of the i n f l u e n c e of t h e p o l y m e r m o r p h o l o g y o n t h e r a t e of b i o e r o s i o n i s p r o v i d e d b y a c o m p a r i s o n of p o l y ( L - l a c t i c a c i d ) a n d p o l y ( D , L - l a c t i c a c i d ) : a l t h o u g h these two polymers have chemically identical b a c k b o n e s t r u c t u r e s a n d a n i d e n t i c a l degree of h y d r o p h o b i c i t y , devices m a d e of poly(Ll a c t i c a c i d ) t e n d to d e g r a d e m u c h s l o w e r t h a n i d e n t i c a l d e v i c e s m a d e o f p o l y p , L - l a c t i c a c i d ) . T h e s l o w e r r a t e of b i o e r o s i o n o f p o l y ( L - l a c t i c a c i d ) i s d u e to t h e f a c t t h a t t h i s s t e r e o r e g u l a r p o l y m e r i s s e m i c r y s t a l l i n e , w h i l e t h e r a c e m i c p o l y ( D , L - l a c t i c acid) i s a m o r p h o u s . L i k e w i s e , a p o l y m e r i n i t s g l a s s y s t a t e i s l e s s p e r m e a b l e to w a t e r t h a n t h e s a m e p o l y m e r w h e n it i s i n i t s r u b b e r y s t a t e . T h i s o b s e r v a t i o n c o u l d be of i m p o r t a n c e i n cases where a n a m o r p h o u s p o l y m e r h a s a g l a s s t r a n s i t i o n t e m p e r a t u r e (Tg) t h a t i s n o t far a b o v e b o d y t e m p e r a t u r e (37 °C). I n t h i s s i t u a t i o n , t h e i n c o r p o r a t i o n of a d r u g i n t o





the p o l y m e r i c m a t r i x c o u l d lower the T g of the "loaded" device below 3 7 °C, r e s u l t i n g i n u n e x p e c t e d a n d a b r u p t c h a n g e s i n t h e b i o e r o s i o n rate. T h e m a n u f a c t u r i n g p r o c e s s m a y a l s o h a v e a s i g n i f i c a n t effect o n the erosion profile. F o r e x a m p l e , M a t h i o w i t z a n d c o w o r k e r s (33) showed that polyanhydride microspheres produced by melt e n c a p s u l a t i o n were very dense a n d eroded slowly, whereas the s a m e m i c r o s p h e r e s , formed b y solvent evaporation, were more p o r o u s (and therefore more water permeable) a n d eroded more rapidly. The above examples illustrate a n important technological p r i n c i p l e i n t h e d e s i g n of d e g r a d a b l e m a t r i x s y s t e m s : T h e b i o e r o s i o n rate of a given p o l y m e r is n o t a n u n c h a n g e a b l e property, b u t d e p e n d s to a very large degree o n r e a d i l y c o n t r o l l a b l e factors s u c h as t h e p r e s e n c e of p l a s t i c i z e r s o r a d d i t i v e s , t h e m a n u f a c t u r i n g p r o c e s s , t h e n a t u r e o f t h e d r u g a n d t h e l e v e l of d r u g l o a d i n g , t h e i n i t i a l m o l e c u l a r w e i g h t o f t h e p o l y m e r , a n d t h e g e o m e t r y of t h e d e v i c e . F r o m a n applied perspective, the most c o m m o n l y investigated d e g r a d a b l e p o l y m e r s for t h e f o r m u l a t i o n o f m a t r i x - t y p e d r u g r e l e a s e s y s t e m s are poly(lactic acid) a n d 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 (22). However, at t h i s point, no i m p l a n t a b l e , d e g r a d a b l e release s y s t e m h a s b e e n a p p r o v e d i n the U S A . O n e of the m o s t a d v a n c e d s y s t e m s is a degradable m a t r i x s y s t e m , developed b y Langer's g r o u p at M I T . T h i s s y s t e m i s u s e d to r e l e a s e a n a n t i n e o p l a s t i c a g e n t f r o m a p o l y a n h y d r i d e m a t r i x (31) a n d i s c u r r e n t l y u n d e r g o i n g p h a s e III clinical trials i n several medical centers i n the U S A . Targeted Drug Delivery T h e b a s i c p r e m i s e of "targeted d r u g delivery" is the a s s u m p t i o n t h a t t h e t h e r a p e u t i c i n d e x of a d r u g c a n be i m p r o v e d w h e n t h e d r u g a c c u m u l a t e s selectively i n specific t i s s u e s , organs, or cell types. D r u g s c a n be targeted b y a wide range of m e c h a n i s m s a n d therefore n u m e r o u s a p p r o a c h e s have b e e n developed, s o m e of w h i c h w i l l be reviewed i n the following sections. O n a very b a s i c level, one c a n d i s t i n g u i s h b e t w e e n insoluble, particulate drug carriers, and soluble, macromolecular drug conjugates. These two designs represent f u n d a m e n t a l l y different a p p r o a c h e s to t h e t a r g e t i n g of d r u g s . F u r t h e r m o r e , o n e h a s to d i s t i n g u i s h b e t w e e n a c t i v e l y a n d p a s s i v e l y t a r g e t e d s y s t e m s . Passively targeted systems utilize existing body m e c h a n i s m s to r e a c h t h e i r d e s t i n a t i o n . F o r e x a m p l e , d u e to t h e f a c t that m a n y particulate d r u g carriers are rapidly t a k e n u p b y the r e t i c u l o e n d o t h e l i a l s y s t e m ( R E S ) , t h e t e n d e n c y of m i c r o p a r t i c u l a t e s to a c c u m u l a t e i n the liver is w e l l d o c u m e n t e d . T h u s , the liver u p t a k e o f m i c r o p a r t i c u l a t e s r e p r e s e n t s p r o b a b l y t h e b e s t s t u d i e d e x a m p l e for passive targeting. I n c o n t r a s t , actively targeted systems utilize a s p e c i f i c b i o l o g i c a l i n t e r a c t i o n to a c t i v e l y s e e k t h e i r t a r g e t . T h e u s e of m o n o c l o n a l antibodies as "targeting moieties" against specific c a n c e r c e l l s r e p r e s e n t s a g o o d e x a m p l e for a c t i v e t a r g e t i n g . O t h e r s p e c i f i c biological interactions, s u c h as the i n t e r a c t i o n between a n enzyme


31

32



a n d its s u b s t r a t e , or the i n t e r a c t i o n between r e c e p t o r c a n a l s o b e e x p l o i t e d for t h e d e s i g n s y s t e m s (42).

a hormone of actively

and its targeted

Insoluble P a r t i c u l a t e Carriers. A d r u g c a r r i e r , a s i m p l i e d b y t h e n a m e , i s a p h a r m a c o l o g i c a l l y i n a c t i v e p o l y m e r w h o s e t a s k i s to c a r r y a d r u g to i t s site of a c t i o n . Microspheres, a n d m i c r o - or nanoparticles b e l o n g to t h e g r o u p of i n s o l u b l e , p a r t i c u l a t e c a r r i e r s . L i p o s o m e s a r e also i m p o r t a n t p a r t i c u l a t e carriers, b u t w i l l not be reviewed here s i n c e they are not polymeric. A p r i m a r y c o n s i d e r a t i o n for t h e u s e of m i c r o p a r t i c u l a t e c a r r i e r s i s biodegradability. A l t h o u g h c r o s s l i n k e d d e r i v a t i v e s of p o l y ( m e t h y l m e t h a c r y l a t e ) o r p o l y ( a c r y l a m i d e ) h a v e b e e n s u g g e s t e d for t h e p r e p a r a t i o n of n a n o - a n d m i c r o p a r t i c l e s , these particles are not r e a d i l y d e g r a d a b l e i n v i v o a n d , w h e n i n j e c t e d or i m p l a n t e d , t e n d to a c c u m u l a t e i n the body u p o n repeated a d m i n i s t r a t i o n . For this reason, nondegradable m i c r o p a r t i c u l a t e carriers are not p r a c t i c a l c a n d i d a t e s for m o s t d r u g d e l i v e r y a p p l i c a t i o n s . O n t h e o t h e r h a n d , p a r t i c l e s c o m p o s e d , for e x a m p l e , of p o l y ( a l k y l 2-cyanoacrylate), copolymers of a c r y l a m i d e and dextran (4 3 ) , derivatives of p o l y ( g l u t a m i c a c i d ) (44), o r p o l y (lactic a c i d ) (22) a r e b i o d e g r a d a b l e . S u c h c a r r i e r s y s t e m s are c u r r e n t l y b e i n g intensely investigated. M i c r o p a r t i c u l a t e c a r r i e r s a r e u s u a l l y passively targeted systems. A s m e n t i o n e d a b o v e , t h e h i g h u p t a k e of m i c r o p a r t i c u l a t e c a r r i e r s b y K u p f f e r c e l l s l o c a t e d i n t h e l i v e r p r o v i d e s a n e x c e l l e n t m e c h a n i s m for the p a s s i v e targeting of the liver. M i c r o p a r t i c u l a t e carriers have also been suggested for o r a l a p p l i c a t i o n s : N e f z g e r et a l . (45) demonstrated t h a t a c e r t a i n f r a c t i o n of o r a l l y administered poly(methyl methacrylate) (PMMA) nanoparticles were systemically absorbed. This surprising result was obtained when radioactively labelled poly(methyl-(l- C)-methacrylate) nanoparticles were orally a d m i n i s t e r e d to r a t s a n d a b o u t 1 0 - 1 5 % o f t h e t o t a l r a d i o a c t i v i t y w a s recovered i n the u r i n e a n d the bile. S i n c e P M M A is biostable, the a u t h o r s suggested that the nanoparticles were indeed absorbed intact f r o m t h e GI t r a c t . 1 4

M a c r o m o l e c u l a r conjugates. M a c r o m o l e c u l a r c o n j u g a t e s a r e u s u a l l y actively targeted systems. A s c h e m a t i c of a m a c r o m o l e c u l a r c o n j u g a t e i s s h o w n i n F i g u r e 4. A c o m p r e h e n s i v e r e v i e w o f t h e l i t e r a t u r e r e l a t i n g to m a c r o m o l e c u l a r c o n j u g a t e s r e v e a l e d s e v e r a l h u n d r e d major p u b l i c a t i o n s w h i c h c a n obviously not be covered w i t h i n the context of t h i s overview. W e w i l l therefore present only s o m e f u n d a m e n t a l c o n s i d e r a t i o n s a n d a few s e l e c t e d s a m p l e s . F o r m o r e i n f o r m a t i o n o n s o l u b l e , m a c r o m o l e c u l a r c a r r i e r s , t h e r e a d e r i s r e f e r r e d to a r e c e n t r e v i e w b y D r o b n i k (46). T h e s u c c e s s f u l d e s i g n of a c l i n i c a l l y u s e f u l , m a c r o m o l e c u l a r c a r r i e r i s a n e x c e e d i n g l y d i f f i c u l t t a s k , a s e v i d e n c e d b y t h e fact t h a t a t r u l y h e r o i c i n t e r n a t i o n a l r e s e a r c h effort h a s so far n o t r e s u l t e d i n a n y s i g n i f i c a n t c l i n i c a l a p p l i c a t i o n of s u c h s y s t e m s . A n often cited r a t i o n a l e for t h e d e s i g n a n d s y n t h e s i s of a m a c r o m o l e c u l a r c a r r i e r i s





the expectation that the macromolecular carrier will prolong the d r u g residence time i n the desired body compartment. In addition, t h e c a r r i e r i s o f t e n c l a i m e d to r e d u c e t h e i m m u n o g e n i c i t y o f t h e d r u g a n d p r o t e c t i t f r o m i n a c t i v a t i o n . F i n a l l y , t h e d e s i g n of a p o l y m e r i c d r u g c o n j u g a t e o f f e r s t h e o p p o r t u n i t y to a t t a c h s p e c i f i c t a r g e t i n g moieties w h i c h s h o u l d provide some control over the b i o d i s t r i b u t i o n of the d r u g . A major p r o b l e m i n the design of m a c r o m o l e c u l a r c a r r i e r s is the t i m i n g o f d r u g r e l e a s e . T h e c a r r i e r i s u s u a l l y e x p e c t e d to b e s t a b l e i n c i r c u l a t i o n for a t l e a s t s o m e t i m e to r e a c h i t s t a r g e t s i t e . O n c e a t i t s target site, however, the attached d r u g m u s t u s u a l l y be released f r o m t h e c a r r i e r i n o r d e r to b e a c t i v e . I n s p i t e o f s o m e i n g e n i o u s w o r k , a t t e m p t i n g to t a i l o r t h e r e l e a s e o f d r u g to s p e c i f i c e n z y m a t i c a c t i v i t i e s or e n v i r o n m e n t s (such as the acidic e n v i r o n m e n t f o u n d i n lysosomes) (47), n o g e n e r a l l y a p p l i c a b l e a p p r o a c h for t h e e x a c t t i m i n g of d r u g c l e a v a g e f r o m t h e c a r r i e r h a s s o far b e e n i d e n t i f i e d . A n o t h e r s e r i o u s p r o b l e m i n t h e e v a l u a t i o n of m a c r o m o l e c u l a r c a r r i e r s i s t h e a l m o s t complete absence of u s e f u l correlations between i n vitro a n d i n vivo testing. O b v i o u s l y , c e l l c u l t u r e s , w i t h t h e i r l a c k of c o m p a r t m e n t a l b a r r i e r s are a g e n e r a l l y p o o r m o d e l s y s t e m for t h e e v a l u a t i o n of m a c r o m o l e c u l a r c a r r i e r s w h o s e a c t i v i t y i s s h a p e d to a l a r g e e x t e n t b y t h e i r a b i l i t y (or i n a b i l i t y ) to c r o s s c o m p a r t m e n t a l b a r r i e r s i n v i v o . O v e r the y e a r s , a w i d e range of p o l y m e r i c b a c k b o n e s , b o t h degradable a n d nondegradable, were explored. Noteworthy are the e a r l y u s e of d e x t r a n s a n d other p o l y s a c c h a r i d e s (48), various p o l y ( a m i n o a c i d s ) s u c h a s p o l y - L - l y s i n e (49) a n d p o l y ( g l u t a m i c a c i d ) (50), a n d d e r i v a t i v e s of p o l y m e t h a c r y l a m i d e (51) as p o l y m e r i c backbones. I n r e c e n t y e a r s , the u s e of n o n d e g r a d a b l e p o l y m e r i c b a c k b o n e s s u c h a s c o p o l y m e r s of m a l e i c a n h y d r i d e a n d d i v i n y l e t h e r , p o l y ( v i n y l a l c o h o l ) , o r d e r i v a t i v e s of p o l y m e t h a c r y l a m i d e has s o m e w h a t d e c r e a s e d i n favor of d e g r a d a b l e p o l y m e r s of w h i c h the p o l y ( a m i n o a c i d s ) a r e o f t e n r e g a r d e d a s m o s t p r o m i s i n g (46). T h e u s e o f p o l y ( e t h y l e n e o x i d e ) (also r e f e r r e d t o a s p o l y ( e t h y l e n e glycol) or P E G ) as a c o p o l y m e r c o m p o n e n t w a s w i d e l y i n v e s t i g a t e d a s a " s o l u b i l i z e r " for d r u g c a r r i e r s t h a t i n c l u d e d m a r g i n a l l y s o l u b l e p o l y m e r s or p a r t i c u l a r l y h y d r o p h o b i c drugs. For example, a n A B type b l o c k c o p o l y m e r of p o l y ( a s p a r t i c acid) w i t h P E G h a s b e e n s t u d i e d a s a w a t e r s o l u b l e m a c r o m o l e c u l a r p r o d r u g for t h e s p a r i n g l y s o l u b l e a n t h r a c y c l i n e a n t i b i o t i c a d r i a m y c i n (52). T h e m a j o r a d v a n t a g e of t h a t c o p o l y m e r o v e r s i m p l e p o l y ( a s p a r t i c a c i d ) w a s t h e r e t e n t i o n of w a t e r s o l u b i l i t y of the conjugate despite the i n t r o d u c t i o n of a large n u m b e r of h y d r o p h o b i c a d r i a m y c i n r e s i d u e s . T h e p o l y m e r h a d a m i c e l l a r s t r u c t u r e i n a q u e o u s buffer w i t h a h y d r o p h i l i c outer s h e l l c o m p r i s e d of P E G a n d a h y d r o p h o b i c i n n e r core of p o l y ( a s p a r t i c acid). After u p t a k e b y target cells, the h y d r o l y s i s of the poly(aspartic acid) b a c k b o n e r e s u l t e d i n the release of a d r i a m y c i n f r o m t h e conjugate. A l t h o u g h a w i d e r a n g e of b i o l o g i c a l i n t e r a c t i o n s c o u l d b e u t i l i z e d for d r u g t a r g e t i n g , p o l y c l o n a l o r m o n o c l o n a l a n t i b o d i e s r e p r e s e n t t h e


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b y far m o s t c o m m o n l y considered targeting moieties. These systems have u s u a l l y b e e n far more active i n vitro t h a n i n vivo. Numerous e x a m p l e s of a n t i b o d y - d r u g , a n t i b o d y - p o l y m e r , or a n t i b o d y - p o l y m e r d r u g conjugates are available i n the literature. F o r example, m o n o c l o n a l a n t i b o d y c o n j u g a t e s of a d r i a m y c i n w i t h a p o l y ( P E G - a s p a r t i c acid) c o p o l y m e r h a v e b e e n i n v e s t i g a t e d for t a r g e t e d d r u g d e l i v e r y [53,54). In m a n y ways, this p a r t i c u l a r m a c r o m o l e c u l a r carrier e n c o m p a s s e s m a n y of the "preferred" s t r u c t u r a l elements: P E G as a solubilizer, a biocompatible, degradable backbone structure, a n d a n i m p o r t a n t antineoplastic agent w i t h significant toxicity that c o u l d be alleviated by a targeted dosage form. E x a m p l e s of S p e c i f i c T a r g e t e d D e l i v e r y S y s t e m s . I n t h e f o l l o w i n g s e c t i o n , s o m e e x a m p l e s of s p e c i f i c t a r g e t e d d e l i v e r y s y s t e m s w i l l b e p r e s e n t e d i n more detail. In a r r a n g i n g t h i s section, we g r o u p e d the d e l i v e r y s y s t e m s b a s e d o n t h e i r m o d e of t a r g e t i n g . This common c l a s s i f i c a t i o n s c h e m e l e a d s to t h e d i s t i n c t i o n b e t w e e n (a) s y s t e m s t h a t a r e m e c h a n i c a l l y p l a c e d i n t o a s p e c i f i c s i t e , (b) p a s s i v e l y t a r g e t e d s y s t e m s , (c) a c t i v e l y t a r g e t e d s y s t e m s , a n d (d) s y s t e m s t h a t u t i l i z e p h y s i c a l m e a n s for d r u g t a r g e t i n g . Mechanically Placed Delivery Systems. In the simplest a p p r o a c h to t a r g e t i n g , a c o n t r o l l e d r e l e a s e s y s t e m i s mechanically placed into a s p e c i f i c s i t e . T h e t a r g e t i n g effect of s u c h a s y s t e m i s b a s e d o n t h e c o n f i n e m e n t o f d r u g r e l e a s e to a c e r t a i n v o l u m e a r o u n d t h e d e l i v e r y system. C u r r e n t l y , i m p l a n t a b l e p u m p s a n d biostable or bioerodible poly m e r i c devices are b e i n g u s e d i n t h i s m a n n e r . A n e x a m p l e of a m e c h a n i c a l l y placed device is the Progestasert Intrauterine Device (IUD), a c o n t r a c e p t i v e s y s t e m t h a t d e l i v e r s 6 5 μg o f p r o g e s t e r o n e for over 4 0 0 days. T h e Progestasert I U D utilizes a d r u g reservoir w i t h a rate l i m i t i n g ethylene-vinyl acetate copolymer m e m b r a n e . Another e x a m p l e is the O c u s e r t p i l o c a r p i n e o p h t h a l m i c i n s e r t for t h e t r e a t m e n t of g l a u c o m a . T h e O c u s e r t i n s e r t is p l a c e d i n the c u l - d e - s a c o f t h e l o w e r e y e l i d . Z e r o o r d e r r e l e a s e of p i l o c a r p i n e t h r o u g h a r a t e l i m i t i n g e t h y l e n e - v i n y l a c e t a t e c o p o l y m e r m e m b r a n e a t r a t e s of e i t h e r 2 0 μg/h ( O c u s e r t P i l o - 2 0 ) or 4 0 \ig/h ( O c u s e r t P i l o - 4 0 ) i s a c h i e v e d for 7 days. A l t h o u g h the O c u s e r t device is inserted o n l y once weekly, it h a s n o t b e c o m e p o p u l a r w i t h g l a u c o m a p a t i e n t s w h o p r e f e r to i n s t i l l t i m o l o l eye d r o p s t w i c e d a i l y . T h e m o u t h i s a l s o a u s e f u l s i t e for m e c h a n i c a l l y p l a c e d d e v i c e s since they c a n be easily inserted a n d removed a n d patient acceptance of the o r a l r o u t e is h i g h . A n e x a m p l e of a n o r a l i n s e r t a b l e s y s t e m i s t h e u s e o f t e t r a c y c l i n e for t h e t r e a t m e n t o f p e r i o d o n t a l d i s e a s e (55). Tetracycline h a s been incorporated into a n ethylene-vinyl acetate c o p o l y m e r m a t r i x for t h e l o n g - t e r m d e l i v e r y of l o w levels of tetracycline. A l t h o u g h t h e d e v i c e i s effective i n p r e v e n t i n g p e r i o d o n t a l d i s e a s e , c o m f o r t a b l e t o o t h a n c h o r i n g d e v i c e s a r e n e e d e d to make this regimen a success. I m p l a n t a b l e s y s t e m s h a v e f o u n d u t i l i t y i n t h e t r e a t m e n t of c e r t a i n





b r a i n t u m o r s . T h e i n t r a c r a n i a l delivery of m i t o m y c i n , a d r i a m y c i n , BCNU and 5-fluorouracil in 10% polymethylmethacrylate (PMMA) c o m p o s i t e s w e r e s h o w n to i n c r e a s e t h e s u r v i v a l o f p a t i e n t s w i t h g l i o b l a s t o m a a n d a n a p l a s t i c a s t r o c y t o m a (56). A n o t h e r e x a m p l e i s t h e u s e of P M M A pellets c o n t a i n i n g m e t h o t r e x a t e to treat b r a i n t u m o r s . Pellets that were i m p l a n t e d i n rat b r a i n t u m o r s were s h o w n to s i g n i f i c a n t l y r e d u c e t u m o r v o l u m e a n d i n c r e a s e the s u r v i v a l of t h e r a t s (57). Passively Targeted Delivery Systems. Passive targeting involves t h e r a n d o m m o v e m e n t o f t h e d e l i v e r y s y s t e m t h r o u g h t h e b o d y to i t s s i t e o f r e l e a s e . P a s s i v e l y t a r g e t e d s y s t e m s u s e n a t u r a l flow i n a r e a s s u c h a s t h e b l o o d s t r e a m o r g a s t r o i n t e s t i n a l t r a c t a n d , at a s p e c i f i c p h y s i o l o g i c a l site of u p t a k e or reconversion, the t h e r a p e u t i c moiety is released. C o l o n i c d r u g delivery is a n e x a m p l e of a n a r e a w h e r e p a s s i v e l y t a r g e t e d d r u g d e l i v e r y d e v i c e s m a y b e effective. O n c e s w a l l o w e d , a c o l o n i c d r u g delivery device w i l l traverse the s m a l l i n t e s t i n e i n a b o u t 1.5 to 4 . 5 h (58). A t t h i s point, it enters the colon. C o l o n i c d r u g delivery strategies u s u a l l y i n c l u d e the u s e of p o l y m e r s or p o l y m e r p r o d r u g s t h a t a r e s u b s t r a t e s for e n z y m e s f o u n d o n l y i n t h e c o l o n ; therefore, the device is protected from digestive enzymes u n t i l it gets to t h e c o l o n . C o l o n specific strategies h a v e i n c l u d e d the delivery of l o w m o l e c u l a r w e i g h t p r o d r u g s (59) a n d p o l y m e r i c p r o d r u g s ( 6 0 ) . T h e s e s y s t e m s release d r u g o n l y i n the p r e s e n c e of g l y c o s i d a s e s or a z o r e d u c t a s e s w h i c h a r e o n l y p r e s e n t i n t h e c o l o n (61). B r o n d s t e d a n d K o p e c e k (17) h a v e s t u d i e d h y d r o g e l s t h a t a r e s u s c e p t i b l e t o azoreductases i n the colon. These authors synthesized hydrogels containing both acidic comonomers and enzymatically degradable azoaromatic crosslinks. T h e gels have a p H s e n s i t i v e s w e l l i n g m e c h a n i s m w i t h m a x i m a l s w e l l i n g a t t h e i n c r e a s e d p H of t h e d i s t a l s m a l l i n t e s t i n e . I n t h e c o l o n t h e gels r e a c h a d e g r e e of s w e l l i n g t h a t m a k e s t h e c r o s s - l i n k s a c c e s s i b l e to a z o r e d u c t a s e s . T h e gel is t h e n degraded a n d the d r u g is released. S a f f r a n et a l . h a v e u s e d a h y d r o p h o b i c a z o p o l y m e r c o a t i n g s u s c e p t i b l e to a z o r e d u c t i o n t o d e l i v e r v a s o p r e s s i n a n d i n s u l i n o r a l l y i n r a t s (10) a n d d o g s (62). I n t h e d o g s t u d y , b o v i n e i n s u l i n w a s m i x e d w i t h 5 - m e t h o x y s a l i c y l c f t e (an absorption enhancer) a n d placed into a gelatin capsule. The capsule w a s c o a t e d w i t h a t e r p o l y m e r of styrene, h y d r o x y e t h y l m e t h a c r y l a t e a n d N,N'-bis-(p-styrylsulphonyl)-4,4 -diaminoazobenzene as a cross l i n k i n g agent. After m u l t i p l e o r a l doses i n dogs, p r o f o u n d decreases i n hepatic glucose production a n d p l a s m a glucagon-like activity were o b s e r v e d . G l y c o s i d i c p o l y s a c c h a r i d e s h a v e a l s o b e e n u s e d for t a r g e t i n g glycosidic enzymes of t h e c o l o n s u c h as β - g l u c o s i d a s e , βg l u c u r o n i d a s e , a n d β-xylodase a s r e p o r t e d b y L a n c a s t e r et a l . (63). ,

Actively Targeted Delivery Systems. D u r i n g the 1970s a n d 1980s u n r e a l i s t i c e x p e c t a t i o n s l e d to p r e d i c t i o n s t h a t a c t i v e l y t a r g e t e d d r u g delivery systems would, w i t h i n a short time, revolutionize the


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treatment of c a n c e r a n d other diseases. D u r i n g t h a t time, t e r m s l i k e " m a g i c b u l l e t " , " g u i d e d m i s s i l e " , " w a r h e a d c a r r i e r " w e r e u s e d to describe actively targeted delivery systems. T h e s e t e r m s are not o n l y a n oversimplification, they are w r o n g given the biological c h a r a c t e r i s t i c s o f a n t i b o d y - a n t i g e n i n t e r a c t i o n s a s c o m p a r e d to t h e b e h a v i o r o f m o d e r n w e a p o n r y . T h e e a r l y r e s e a r c h efforts o n a c t i v e l y t a r g e t e d delivery systems were uniformly u n s u c c e s s f u l a n d consequently not a single antibody-based cancer therapeutic is c u r r e n t l y on the m a r k e t (there a r e , h o w e v e r , s o m e a n t i b o d y - b a s e d d i a g n o s t i c s a v a i l a b l e ) . T h e p u r p o s e o f a c t i v e l y t a r g e t e d d r u g d e l i v e r y s y s t e m s i s to a l t e r t h e n a t u r a l d i s t r i b u t i o n p a t t e r n to d i r e c t d r u g s to s p e c i f i c o r g a n s , t i s s u e s o r c e l l s . I n p r i n c i p l e , a l a r g e v a r i e t y of b i o l o g i c a l i n t e r a c t i o n s c a n b e u s e d for t a r g e t i n g p u r p o s e s . I n p r a c t i c e , h o w e v e r , t h e s p e c i f i c i n t e r a c t i o n s b e t w e e n a n t i b o d i e s a n d their a n t i g e n s are most commonly employed. T h e r e s e a r c h effort o n a c t i v e l y t a r g e t e d d r u g d e l i v e r y s y s t e m s i s fueled by powerful b u s i n e s s interests, since cancer chemotherapeutics currently constitute a $4 billion/year market. Over 30 N o r t h A m e r i c a n a n d E u r o p e a n c o m p a n i e s are developing a n t i b o d y based therapeutics. W h i l e the d e v e l o p m e n t of c l i n i c a l l y u s e f u l targeted d r u g delivery systems was technologically not feasible d u r i n g the 1970s a n d 1980s, significantly improved antibodies a n d superior c h e m i c a l m e t h o d s for t h e a s s e m b l y of m a c r o m o l e c u l a r c o n j u g a t e s h a v e n o w b e c o m e a v a i l a b l e . D u e to t h e s e a d v a n c e s , s e v e r a l p r o d u c t s are c u r r e n t l y i n clinical trials a n d will become available i n the near future. T h e s e p r o d u c t s will be u s e d i n c o n j u n c t i o n w i t h c o n v e n t i o n a l therapies, rather t h a n replacing them. A m a j o r t e c h n o l o g i c a l p r o b l e m of a c t i v e l y t a r g e t e d d r u g d e l i v e r y s y s t e m s r e l a t e s to t h e s o u r c e of the a n t i b o d y . S i n c e for e t h i c a l r e a s o n s h u m a n s c a n n o t be u s e d as h o s t s i n the p r o d u c t i o n of m o n o c l o n a l a n t i b o d i e s (MAb), h u m a n m o n o c l o n a l a n t i b o d i e s a g a i n s t h u m a n c a n c e r s a r e n o t r e a d i l y a v a i l a b l e . M o s t of t h e e a r l y w o r k o n actively targeted d r u g delivery systems was therefore done w i t h m u r i n e antibodies. W h e n s u c h antibodies are injected into h u m a n s , the h u m a n i m m u n e s y s t e m recognizes the m u r i n e a n t i b o d y as foreign. The subsequent " h u m a n antimouse antibody" (HAMA) response neutralizes the m u r i n e antibody a n d t h u s eliminates its targeting effect. I n a d d i t i o n , m u r i n e a n t i b o d i e s h a v e a v e r y s h o r t h a l f - l i v e i n c i r c u l a t i o n w h i c h i s a c c e p t a b l e for d i a g n o s t i c a p p l i c a t i o n s b u t a s e v e r e d i s a d v a n t a g e for t h e r a p e u t i c a p p l i c a t i o n s . C u r r e n t l y , c h i m e r i c antibodies, h u m a n i z e d antibodies, a n d antibody fragments are being e x p l o r e d i n a n a t t e m p t to o v e r c o m e t h e l i m i t a t i o n s o f n o n - h u m a n antibodies. A n o t h e r s e r i o u s p r o b l e m is posed by the a n t i b o d y targets t h e m selves. A l t h o u g h m o n o c l o n a l antibodies are h i g h l y specific i n their i n t e r a c t i o n w i t h a n t i g e n s , the effectiveness of t h e i r a c t i o n a s t a r g e t i n g m o i e t i e s d e p e n d s o n the p r o p e r c h o i c e of t h e target. P o t e n t i a l t a r g e t s i n c l u d e , for e x a m p l e , d i f f e r e n t i a t i o n a n t i g e n s , o n c o g e n e p r o d u c t s , a n d g r o w t h f a c t o r s . T h e n e e d to c a r e f u l l y c h o o s e t h e t a r g e t i s i l l u s t r a t e d b y t h e b e h a v i o r of m a n y t u m o r - a s s o c i a t e d





differentiation antigens w h i c h are n o r m a l l y expressed b y fetal cells a n d are often p r e s e n t i n low levels o n n o r m a l cells. Furthermore, t u m o r - a s s o c i a t e d differentiation antigens are not a l w a y s b o u n d to the cell m e m b r a n e b u t c a n be found i n c i r c u l a t i o n . C i r c u l a t i n g antigens m a y r e a c t w i t h t h e a n t i b o d y of the d r u g delivery s y s t e m - t h e r e b y p r e v e n t i n g t h e s y s t e m to r e a c h i t s i n t e n d e d t a r g e t . T h e actively targeted d r u g delivery systems that are now b e c o m i n g a v a i l a b l e for c l i n i c a l t r i a l s a r e s i m p l e a n t i b o d y - d r u g conjugates t h a t do not c o n t a i n the p o l y m e r i c b a c k b o n e s h o w n i n F i g u r e 4. A l t h o u g h it w o u l d u s u a l l y b e a d v a n t a g e o u s to a t t a c h a d r u g l o a d e d p o l y m e r to t h e a n t i b o d y ( r a t h e r t h a n a t t a c h i n g m u l t i p l e d r u g u n i t s to t h e a n t i b o d y d i r e c t l y ) , t h e p o l y m e r i c c a r r i e r c a n b e a s e r i o u s s o u r c e of c o m p l i c a t i o n s . F i r s t , m o s t a n t i c a n c e r d r u g s h a v e to b e i n t e r n a l i z e d b y t h e t a r g e t c e l l i n o r d e r to b e effective. O n e w a y to a c h i e v e t h i s g o a l i s to u s e " i n t e r n a l i z i n g " a n t i b o d i e s , e.g., a n t i b o d i e s t h a t a r e n a t u r a l l y t a k e n u p b y t h e c e l l . T h e a t t a c h m e n t of a l a r g e p o l y m e r to t h e a n t i b o d y m a y i n t e r f e r e w i t h t h e p r o c e s s of i n t e r n a l i z a t i o n a n d t h u s r e n d e r t h e s y s t e m ineffective. Second, most polymeric d r u g conjugates have a tend e n c y t o b e t a k e n u p b y e l e m e n t s of t h e r e t i c u l o e n d o t h e l i a l s y s t e m ( R E S ) . T h i s t e n d e n c y c a n l e a d to t h e p r e d o m i n a n t a c c u m u l a t i o n of t h e p o l y m e r i c c o n j u g a t e i n t h e l i v e r , p r e v e n t i n g t h e s y s t e m to r e a c h its i n t e n d e d target. F u r t h e r r e s e a r c h is therefore needed t o w a r d the identification of polymeric carriers that, b y themselves, s h o w as little n o n s p e c i f i c u p t a k e as possible. One s u c h carrier is a recently s y n t h e s i z e d , h i g h l y w a t e r s o l u b l e p o l y (ether u r e t h a n e ) d e r i v e d f r o m P E G a n d t h e n a t u r a l a m i n o a c i d L - l y s i n e (64-66). In preliminary b i o d i s t r i b u t i o n s t u d i e s , t h i s c a r r i e r w a s s h o w n to r e m a i n i n t h e b l o o d c o m p a r t m e n t w i t h o u t o r g a n - s p e c i f i c u p t a k e (67). Physically Controlled Targeted Delivery Systems. U s i n g p h y s i c a l controls s u c h as localized magnetic fields, p H differences or t e m p e r a t u r e gradients, a p h y s i c a l l y controlled delivery s y s t e m c a n be d i r e c t e d to a s p e c i f i c s i t e o r i t s c o n t e n t s c a n b e r e l e a s e d a t a c e r t a i n site. O n e of the p r o m i s i n g d e v e l o p m e n t s i n p h y s i c a l l y c o n t r o l l e d d e l i v e r y s y s t e m s i s t h e u s e of l o c a l i z e d m a g n e t i c f i e l d s . W i d d e r a n d coworkers (68) w e r e t h e f i r s t to r e p o r t t h e u s e o f m a g n e t i c a l l y r e s p o n s i v e m i c r o s p h e r e s for t a r g e t e d d e l i v e r y . M o r e r e c e n t l y , G u p t a a n d H u n g (69) s t u d i e d t h e effects o f m a g n e t i c a l b u m i n m i c r o s p h e r e s i n the delivery of d o x o r u b i c i n , a n a n t i c a n c e r agent, i n rats. After a n i n t r a v e n o u s i n j e c t i o n of d o x o r u b i c i n m i c r o s p h e r e s , a m a g n e t i c f i e l d w a s a p p l i e d to t h e t a i l for 3 0 m i n . T h e m a g n e t i c f i e l d r e s u l t e d i n a significantly higher d o x o r u b i c i n concentration i n the tail as c o m p a r e d to the c o n c e n t r a t i o n m e a s u r e d i n a p p r o p r i a t e c o n t r o l s t u d i e s . In a d d i t i o n , t h e d e l i v e r y of d o x o r u b i c i n to a l l n o n - t a r g e t t i s s u e s , i n c l u d i n g the liver a n d heart, was s u b s t a n t i a l l y reduced. Although r e p o r t s of the u s e of p o l y m e r i c m a g n e t i c m i c r o s p h e r e s i n the l i t e r a t u r e a r e l a c k i n g , t h e s t u d i e s of G u p t a et a l . (69) m a y l e a d t o t h e d e v e l o p m e n t of m a g n e t i c a l l y t a r g e t e d p o l y m e r i c s y s t e m s .


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Summary After a n i n i t i a l p e r i o d of r a p i d a d v a n c e s i n the f u n d a m e n t a l u n d e r s t a n d i n g of p o l y m e r i c d r u g delivery s y s t e m s a n d a p e r i o d of excessive e x p e c t a t i o n s , t h e f i e l d i s n o w s h o w i n g s i g n s of s c i e n t i f i c m a t u r i t y . T h e o f t e n s i g n i f i c a n t r e s e a r c h efforts d u r i n g t h e 1 9 7 0 s a n d 1 9 8 0 s ( w h i c h were a l m o s t a l w a y s u n s u c c e s s f u l f r o m a c o m m e r c i a l p o i n t of v i e w ) , a r e n o w s t a r t i n g to " p a y o f f : A w a v e of t r a n s d e r m a l delivery s y s t e m s h a s b e e n i n t r o d u c e d i n t o t h e m a r k e t o v e r t h e l a s t few y e a r s a n d several a d d i t i o n a l systems are i n advanced c l i n i c a l trials. The f i n a l a p p r o v a l of the c o n t r a c e p t i v e device N o r p l a n t i n 1 9 9 0 i n t r o d u c e d the first polymeric, i m p l a n t a b l e device into the U S m a r k e t . T h e p o l y a n h y d r i d e s u s e d as c h e m o t h e r a p e u t i c delivery s y s t e m for b r a i n t u m o r s m a y b e c o m e the first F D A approved i m p l a n t a b l e polymeric matrix system based on a degradable polymer. Finally, a n u m b e r of targeted a n t i c a n c e r s y s t e m s u s i n g a n t i b o d y - d r u g (but n o t yet antibody-drug-polymer) conjugates w i l l become available i n the near future. T h e e x p e r i e n c e of t h e l a s t 2 0 y e a r s h a s s h o w n t h a t t h e r e i s a strong connection between advances i n the m a t e r i a l sciences (particularly polymer chemistry) a n d advances i n the design a n d i m p l e m e n t a t i o n of n e w d r u g delivery s y s t e m s . In this context, the s l o w p a c e i n w h i c h n e w , d e g r a d a b l e p o l y m e r s a r e b e i n g a d o p t e d for d r u g d e l i v e r y a p p l i c a t i o n s i s a c o n c e r n . I n a n a t t e m p t to r e d u c e t h e c o s t o f t h e F D A a p p r o v a l p r o c e s s for n e w d r u g d e l i v e r y s y s t e m s , industrial development efforts h a v e s t r o n g l y favored t h e w e l l e s t a b l i s h e d p o l y m e r s of l a c t i c a n d g l y c o l i c a c i d , a l m o s t t o t h e e x c l u s i o n of p r o m i s i n g a l t e r n a t i v e s s u c h as poly(ortho esters), poly(hydroxybutyrates), pseudo-poly (amino acids), p o l y p h o s p h a z e n e s , a n d a n u m b e r of n a t u r a l p o l y m e r s s u c h a s d e r i v a t i v e s o f c e l l u l o s e , a l b u m i n , collagen, or gelatin. T h e s u c c e s s f u l d e v e l o p m e n t of a w i d e range of degradable delivery systems w i l l a l m o s t c e r t a i n l y d e p e n d o n t h e a v a i l a b i l i t y o f a w i d e r c h o i c e of d e g r a d a b l e p o l y m e r s . C u r r e n t l y , o n e of t h e m o s t i m p o r t a n t c h a l l e n g e s i n t h e d e v e l o p m e n t o f c o n t r o l l e d r e l e a s e s y s t e m s i s t h e d e s i g n of s y s t e m s t h a t a r e c a p a b l e o f m o d u l a t e d r e l e a s e p r o f i l e s , i n r e s p o n s e to a n e x t e r n a l s t i m u l u s o r i n r e s p o n s e to a b i o f e e d b a c k m e c h a n i s m . I n t h e a r e a o f t a r g e t e d d e l i v e r y s y s t e m s , o n e o f t h e m o s t s i g n i f i c a n t c h a l l e n g e s i s to b e t t e r u n d e r s t a n d h o w the b i o l o g i c a l p r o p e r t i e s of p o l y m e r i c d r u g c o n j u g a t e s c a n b e i m p r o v e d i n o r d e r to o p t i m i z e t h e i n v i v o p e r f o r m a n c e of t h e s e s y s t e m s . Acknowledgments J o a c h i m K o h n a c k n o w l e d g e s the s u p p o r t of a N I H R e s e a r c h Development Award (GM00550).


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