Controlled Release Polymeric Formulations - American Chemical

1

Polymers i n C o n t r o l l e d Release T e c h n o l o g y D. R. PAUL Downloaded by UNIV OF ROCHESTER on June 11, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0033.ch001

Department of Chemical Engineering, University of Texas, Austin, Texas 78712

Controlled release technology emerged a c t i v e l y from the 1960's with promises to solve a d i v e r s i t y of problems that have i n common the application of some active agent to a system with the objective of accomp l i s h i n g a s p e c i f i c purpose while avoiding certain other possible responses this agent might cause. A number of techniques for effecting controlled release have been i d e n t i f i e d and analyzed, and most of these have been considered for or embodied in commercial devices or formulations which already are or soon w i l l be on the market. Most of these concepts have been described in the l i t e r a t u r e (patents, j o u r n a l s , books, etc.) The proceedings of previous symposia (1-3) and recent reviews (4-16) provide a rapid way to learn the present state of the art of this technology. One of the common features of many of these techniques or formulations i s the judicious selection of a polymeric material to act as a rate c o n t r o l l i n g device, container, or c a r r i e r for the agent to be released. The contents of this book are the results of an American Chemical Society Symposium organized primarily to emphasize the role of the polymer and i t s selection as opposed to focusing on a p a r t i c u l a r application or methodology although aspects of the l a t t e r are included by necessity. The polymer choices i n some cases are the r e s u l t of sophisticated considerations while in others evolution from h i s t o r i c a l successes had dictated this s e l e c t i o n . Both extremes i l l u s t r a t e the considerable opportunity for t a i l o r i n g polymers to meet the demands of this developing technology. The purposes of this introductory chapter are to make this book somewhat more autonomous and, therefore, 1 In Controlled Release Polymeric Formulations; Paul, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

Downloaded by UNIV OF ROCHESTER on June 11, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0033.ch001

2

CONTROLLED RELEASE

POLYMERIC FORMULATIONS

h o p e f u l l y o f more v a l u e t o t h e r e a d e r by p l a c i n g i t s contents i n perspective by r e v i e w i n g b r i e f l y previous developments i n concepts, techniques, p r i n c i p l e s , a r e a s o f a p p l i c a t i o n , and c o m m e r c i a l p r o d u c t s . T h i s p u r p o s e i s l a r g e l y f u l f i l l e d by i n c l u d i n g i n the b i b l i o g r a p h y a compendium o f symposium p r o c e e d i n g s , r e v i e w a r t i c l e s , b o o k s , and o t h e r r e f e r e n c e s which have been s e l e c t e d t o p r o v i d e t h e r e a d e r w i t h a quick i n t r o d u c t i o n to the l i t e r a t u r e of t h i s f i e l d . F r o m t h e s e r e f e r e n c e s a n d t h e comments t h a t follow, the r e a d e r w i l l see t h a t t h e p r e s e n t p a p e r s d e a l w i t h o n l y some o f t h e c o n c e p t s w h i c h h a v e d e v e l o p e d i n t h i s a r e a a l t h o u g h a b r o a d and i m p o r t a n t s a m p l i n g i s represented. Rationale

f o r Controlled

Release

C o n v e n t i o n a l l y , a c t i v e agents a r e administered to a system by n o n - s p e c i f i c , p e r i o d i c application. For example, i n m e d i c i n e drugs a r e i n t r o d u c e d a t p e r i o d i c i n t e r v a l s by i n g e s t i o n of p i l l s , l i q u i d s , e t c . o r by i n j e c t i o n and then d i s t r i b u t e d t h r o u g h o u t much o f t h e b o d y r a t h e r t h a n d i r e c t e d t o a s p e c i f i c target. Similarly i n agricultural practice, fertil i z e r s , p e s t i c i d e s and t h e l i k e a r e d i s t r i b u t e d t o c r o p s a t p e r i o d i c i n t e r v a l s by b r o a d c a s t i n g , s p r a y ing, e t c . Immediately f o l l o w i n g these a p p l i c a t i o n p u l s e s the c o n c e n t r a t i o n of the a c t i v e agent r i s e s to h i g h l e v e l s system-wide. I n some c a s e s , t h e s e i n i t i a l l y h i g h c o n c e n t r a t i o n s may p r o d u c e u n d e s i r e d side e f f e c t s e i t h e r to the t a r g e t area of the system and/or the environment around the t a r g e t . As t i m e passes a f t e r t h i s spike of a c t i v e agent, i t s concent r a t i o n begins to f a l l because of n a t u r a l processes such as e l i m i n a t i o n from t h e system, consumption, o r deterioration. Before the next a p p l i c a t i o n , the c o n c e n t r a t i o n o f t h e a c t i v e a g e n t may f a l l b e l o w t h e necessary l e v e l f o r the desired response. Thus p e r i o d i c a p p l i c a t i o n s a r e f r u s t r a t e d by c o n c e n t r a t i o n s o f a c t i v e a g e n t w h i c h may be a l t e r n a t e l y t o o h i g h o r t o o l o w w i t h i n t h e same c y c l e when t h e t i m e b e t w e e n d o s e s i s l o n g w h i l e o n t h e o t h e r h a n d more frequent a p p l i c a t i o n of s m a l l e r doses r e s u l t s i n more i n c o n v e n i e n c e a n d e x p e n s e o f a p p l i c a t i o n . In a d d i t i o n , a c y c l i c regime i s u s u a l l y r a t h e r ineffic i e n t i n that a considerable f r a c t i o n of the a c t i v e agent never gets to perform the intended function e i t h e r because of d e t e r i o r a t i o n or l o s s to the system

In Controlled Release Polymeric Formulations; Paul, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.


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Polymers

3

environment. I n many c a s e s t h e l a t t e r may be q u i t e s e r i o u s , and i n a l l c a s e s b o t h f a c t o r s i n f l a t e t h e cost of the treatment. C e r t a i n l y a more d e s i r a b l e r e g i m e w o u l d be t o r e l e a s e t h e a c t i v e a g e n t a t a c o n t r o l l e d r a t e that m a i n t a i n s i t s c o n c e n t r a t i o n i n the s y s t e m w i t h i n o p t i m u m l i m i t s , a n d i t w o u l d be e v e n b e t t e r to r e l e a s e t h i s agent d i r e c t l y to the t a r g e t a r e a o f t h e s y s t e m i f one e x i s t s o r c a n be i d e n t i f i e d . The l a t t e r a r e t h e o b j e c t i v e s o f c o n t r o l l e d r e l e a s e t e c h n o l o g y i n g e n e r a l whether the a c t i v e agent i s a d r u g , p e s t i c i d e , or sex a t t r a c t a n t or whether the p u r p o s e i s t o c o n t r o l t h e g r o w t h o f weeds o r t o p r e vent b a r n a c l e s from f o r m i n g . Areas

of

Application

C o n t r o l l e d r e l e a s e t e c h n o l o g y has been c o n s i d e r e d f o r a wide v a r i e t y of a p p l i c a t i o n s of which a l a r g e f r a c t i o n are e i t h e r m e d i c a l l y r e l a t e d or f o r p e s t control. Some o f t h e p a p e r s i n c o r p o r a t e d i n t h i s b o o k a r e g e n e r a l i n s c o p e and t h e f o r m u l a t i o n s o r p r i n c i p l e s d i s c u s s e d m i g h t be a p p l i c a b l e t o a number of d i f f e r e n t a r e a s ; however, most d e a l w i t h p a r t i c u lar objectives. I t i s of i n t e r e s t , t h e r e f o r e , to summarize t h e s e o b j e c t i v e s h e r e and t o m e n t i o n e x amples o f o t h e r s p e c i f i c problems of a c t i v e i n t e r e s t which a r e not d e a l t w i t h i n t h i s book. In the m e d i c a l a r e a , c o n t r a c e p t i o n or f e r t i l i t y c o n t r o l h a s h i s t o r i c a l l y b e e n one o f t h e m o s t p u b l i c i z e d a p p l i c a t i o n s , and t h i s i s r e f l e c t e d i n t h e papers which f o l l o w . H o w e v e r , a l s o c o v e r e d h e r e more b r i e f l y , are f o r m u l a t i o n s to d e l i v e r n a r c o t i c antagon i s t s , f l u o r i d e f o r d e n t a l p u r p o s e s a n d d r u g s t o comb a t c a n c e r and c a r d i a c a r r h y t h m i a and a d r u g t o i n duce h y p e r t e n s i o n f o r e x p e r i m e n t a l s t u d i e s . Many o f these papers d e a l w i t h t e c h n i q u e s of g e n e r a l a p p l i c a b i l i t y as d r u g d e l i v e r y s y s t e m s . An e x a m p l e o f a m e d i c a l a r e a n o t c o v e r e d h e r e i s t h e r e c e n t l y commerc i a l i z e d d e v i c e f o r c o n t r o l of glaucoma (8). A number o f t h e f o l l o w i n g p a p e r s d e a l w i t h t h e c o n t r o l of p e s t s s u c h as s n a i l s , weeds, m a r i n e f o u l ing organisms, r o a c h e s , f l y s through the r e l e a s e of t o x i c a n t s or pheromones. None o f t h e p r e s e n t p a p e r s d e a l i n d e t a i l w i t h the r e l e a s e of f e r t i l i z e r s , p e s t i c i d e s , or growth r e g u l a t o r s f o r a g r i c u l t u r a l purposes but a c t i v i t i e s i n these a r e a s are summarized by one o f t h e a u t h o r s .


CONTROLLED

4


Techniques

and R e l e a s e

RELEASE POLYMERIC

FORMULATIONS

Kinetics

One o f t h e c e n t r a l p r o b l e m s i n c o n t r o l l e d r e l e a s e formulations i s t o combine t h e a c t i v e agent w i t h i t s c a r r i e r i n an e c o n o m i c a l manner y e t a c h i e v e a r e l e a s e p r o f i l e t h a t b e s t f i t s t h e s i t u a t i o n . T h e s e two d e s i r e s a r e o f t e n i n o p p o s i t i o n o f one a n o t h e r s o comp r o m i s e s must be made. Frequently the desired release p r o f i l e i s a constant rate of d e l i v e r y of the a c t i v e agent which i n analogy w i t h c h e m i c a l k i n e t i c s has become known a s a " z e r o o r d e r " p r o c e s s s i n c e i t d o e s n o t d e p e n d o n how much o f t h e a g e n t h a s b e e n d e l i v e r e d o r remains. Many o f t h e f o r m u l a t i o n s u s e d i n c o n t r o l l e d r e l e a s e t e c h n o l o g y do n o t m e e t t h i s o b j e c t i v e . At t h i s p o i n t i t w i l l be u s e f u l b a c k g r o u n d t o c a t e g o r i z e as g e n e r a l l y a s p o s s i b l e t h e t e c h n i q u e s o f f o r m u l a t i o n t h a t a r e employed i n t h e s u b s e q u e n t p a p e r s and t o d i s cuss t h e i r inherent r e l e a s e k i n e t i c c h a r a c t e r i s t i c s . F o l l o w i n g t h i s , some o t h e r t e c h n i q u e s n o t e m p l o y e d h e r e w i l l be m e n t i o n e d . The c l a s s i f i c a t i o n scheme p r e f e r r e d h e r e d i v i d e s the d e v i c e s o f i n t e r e s t i n t o the f o l l o w i n g b a s i c types w h i c h i n some c a s e s may be c o m b i n e d i n v a r i o u s w a y s : I.

Erodible

Devices

that

Disappear

In t h i s c a t e g o r y t h e a c t i v e agent i s r e l e a s e d as t h e c a r r i e r i s e r o d e d away b y t h e e n v i r o n m e n t t h r o u g h p h y s i c a l p r o c e s s e s s u c h as d i s s o l u t i o n i n g o r by c h e m i c a l p r o c e s s e s such as h y d r o l y s i s of t h e polymer backbone o r c r o s s l i n k s . T h e k i n e t i c s o f r e l e a s e c a n n o t be s i m p l y s t a t e d s i n c e t h e y depend on t h e d e t a i l s o f t h e e r o s i o n mechanism and g e o m e t r y . The c e n t r a l d i s t i n c t i o n i s the complete disappearance of the device i n time which has obvious advantages p r o v i d i n g the e r o s i o n p r o d u c t s a r e o f no h e a l t h o r e n v i r o n m e n t a l concern. II.

Membrane E n c a p s u l a t e d

Reservoir

Devices

I n t h i s c a t e g o r y a r a t e c o n t r o l l i n g membrane completely encloses a c a v i t y which contains the a c t i v e agent a p p r o p r i a t e l y d i s p e r s e d . These systems have a l s o been r e f e r r e d t o as depot d e v i c e s (8). T h e memb r a n e may be p o r o u s o r n o n - p o r o u s , a n d i n t h e c a s e o f t h e l a t t e r t h e e n v i r o n m e n t a l f l u i d s may o r may n o t a p p r e c i a b l y s w e l l t h e membrane. The m o s t u s e f u l s i t u a t i o n i s when t h e r e s e r v o i r c o n t a i n s a s u s p e n s i o n o f the a c t i v e agent i n a f l u i d s i n c e t h i s w i l l m a i n t a i n a


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Polymers


constant a c t i v i t y of the agent i n the r e s e r v o i r u n t i l the excess has been removed. This situation creates a c o n s t a n t s t e a d y - s t a t e r e l e a s e r a t e by d i f f u s i o n a c r o s s t h e membrane a s i l l u s t r a t e d b e l o w f o r an i d e a l ized situation:

Sink

S = surface area D - diffusion coefficient of a c t i v e agent i n membrane C

m

s

= s o l u b i l i t y of a c t i v e a g e n t i n membrane

I f the a c t i v e agent i s t o t a l l y d i s s o l v e d i n the r e s e r v o i r f l u i d , then i t s a c t i v i t y w i l l change and t h e r e l e a s e r a t e w i l l d e c a y more o r l e s s e x p o n e n t i a l l y w i t h time as expected f o r " f i r s t o r d e r " k i n e t i c s . T h e s e d e v i c e s may be r a t h e r l a r g e ( m a c r o e n c a p s u l a t i o n ) or very s m a l l i n which case microencapsulation i s the usual terminology (10-16). In g e n e r a l the r e l e a s e p r o f i l e f o r e n c a p s u l a t e d s y s t e m s h a s t h e f o r m shown b y t h e g r a p h a t t h e t o p o f the next page. The d u r a t i o n and r a t e f o r e a c h o f t h e t h r e e s t a g e s shown c a n u s u a l l y b e e n g i n e e r e d within c e r t a i n l i m i t s by t h e d e s i g n o f t h e d e v i c e . A s p e c i a l c a s e o f e n c a p s u l a t e d d e v i c e s d e p e n d s on r u p t u r e o f t h e membrane by some m e c h a n i c a l a c t i o n t o r e l e a s e the a c t i v e agent ( 1 3 ) .



6

CONTROLLED RELEASE POLYMERIC

—

FORMULATIONS

^

time III.

Matrix

Devices

I n t h i s t y p e o f s y s t e m t h e r e i s no membrane p e r se b u t r a t h e r t h e a c t i v e a g e n t i s d i s p e r s e d i n a c a r r i e r - u s u a l l y a polymer - from which i t i s u l t i mately extracted. These have a l s o been r e f e r r e d t o as m o n o l i t h s (8) and have o b v i o u s a d v a n t a g e s o f f a b r i c a t i o n , b u t g e n e r a l l y t h e y do n o t y i e l d " z e r o order" release kinetics. M a t r i x d e v i c e s may b e d i v i d e d i n t o two c a t e g o r i e s d e p e n d i n g o n t h e m e c h a n i s m b y w h i c h t h e agent i s r e l e a s e d : A. R e l e a s e Caused by S i m p l e D i f f u s i o n o f A g e n t . I n t h i s c a s e t h e a c t i v e a g e n t a l w a y s h a s some m o b i l i t y w i t h i n t h e c a r r i e r a n d i t s r e l e a s e d e p e n d s on t h e j u x taposition of a suitable exterior sink. We c a n f u r t h e r d i v i d e t h i s c a t e g o r y d e p e n d i n g on w h e t h e r t h e i n i t i a l l o a d i n g p e r u n i t volume of the agent w i t h i n t h e m a t r i x , A, e x c e e d s t h e a g e n t ' s s o l u b i l i t y i n t h e matrix, C , or not * s 1.

A < C s

For t h i s s i t u a t i o n a l l o f the agent a t e q u i l b r i u m i s d i s s o l v e d i n t h e m a t r i x and r e l e a s e i n v o l v e s i t s d i f f u s i o n from the d e v i c e f o l l o w i n g simple notions s i m i l a r t o d e s o r p t i o n a s t r e a t e d i n most c l a s s i c a l w o r k s o n d i f f u s i o n ( 1 7 - 1 9 , 2 2 ) . T h e t o t a l amount


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r e l e a s e d i n time t , Μ , f o l l o w s the u s u a l V T relation as shown below u n t i l about 6 0 % has been removed and then the r a t e f a l l s o f f more r a p i d l y .

2.

A > C

s Γη t h i s c a s e , t h e e x c e s s a g e n t above t h a t w h i c h is dissolved at equilibrium i s dispersed i n the matrix as s m a l l p a r t i c l e s . T h e d e t a i l s o f t h e e x t r a c t i o n may be v e r y c o m p l i c a t e d ; h o w e v e r , f o r t h e u s u a l c a s e when d i f f u s i o n i s r a t e l i m i t i n g r a t h e r than other processes s u c h a s d i s s o l u t i o n i n g , H i g u c h i ( 2 5 , 2 6 ) h a s shown t h a t a very simple but extremely c l e v e r pseudosteady-state analysis describes the release rather a c c u r a t e l y (30). The f i g u r e a t t h e t o p o f t h e n e x t p a g e shows t h e p h y s i c a l picture envisioned. The m a t h e m a t i c a l result H i g u c h i o b t a i n e d f o r t h e r e l e a s e r a t e from p l a n a r geometries i s / DC^(A

- 1/2 C J '


8


FORMULATIONS

·# · ; • #· ι #

···

ΦΦ

·-;>: φ

9

m

core

of undissolved

agent

.region depleted of u n d i s s o l v e d agent

Φ

···/·


% $ %$

ν Λ

ί

: t · ί

The r e l e a s e i n t h i s s i t u a t i o n f o l l o w s t h e same V7 d e p e n d e n c e t h a t e x i s t s when A < C ; h o w e v e r , t h e d e p e n d e n c e o f t h e r a t e o n l o a d i n g f A, i s n o t t h e same. While n e i t h e r s i t u a t i o n gives true "zero order" r e l e a s e p r o f i l e s , i t i s g e n e r a l l y f e l t that the r a t e c h a r a c t e r i s t i c s c a n be made a d e q u a t e f o r some p u r p o s e s by p r o p e r d e s i g n , a n d t h i s d r a w b a c k m u s t b e w e i g h e d a g a i n s t t h e e a s e a n d economy o f f a b r i c a t i n g s u c h devices. The H i g u c h i m o d e l h a s b e e n e x t e n d e d t o o t h e r g e o m e t r i c a l s h a p e s ( 2 6 , 27) a n d t o i n c l u d e b o u n d a r y l a y e r r e s i s t a n c e s (28, 30). Β, R e l e a s e T r i g g e r e d by I n g r e s s i o n o f E n v i r o n mental Agent. I n t h i s c a s e t h e a g e n t may be d i s persed w i t h i n the matrix e i t h e r p h y s i c a l l y or chemi c a l l y bound t o i t , b u t i n e i t h e r c a s e i t i s i n i t i a l l y not m o b i l e f o r p h y s i c a l d i s p e r s i o n s t h i s may be owing to v e r y s m a l l d i f f u s i o n r a t e s . I t s r e l e a s e may be t r i g g e r e d by t h e p e n e t r a t i o n o f some e n v i r o n m e n t a l agent, e.g. water, i n t o the m a t r i x . T h i s event could lead t o a chemical r e a c t i o n to unbind the agent, e.g. h y d r o l y s i s , or simply to p l a s t i c i z e the matrix to a l l o w p h y s i c a l l y bound m o l e c u l e s t o d i f f u s e . The r e l e a s e r a t e may be c o n t r o l l e d b y t h e p e n e t r a t i o n o f the e n v i r o n m e n t a l agent o r t h e r e a c t i o n i t produces o r some c o m b i n a t i o n t h e r e o f a n d t h e n t h e e x a c t f o r m of t h e r a t e depends on t h e d e t a i l s o f t h e p a r t i c u l a r system. T h i s c l a s s of d e v i c e s d i f f e r s from e r o d i b l e systems i n that the matrix remains p h y s i c a l l y i n t a c t .


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IV.

9

Polymers

Reservoir

Devices

Without

a Membrane

This f i n a l category of devices covered i n t h i s book c o n f i n e s t h e a c t i v e a g e n t i n a r e s e r v o i r b u t does n o t e m p l o y a n y membrane t o c o n t r o l i t s r e l e a s e . A s i m p l e example i s h o l l o w f i b e r s which h o l d t h e agent i n t h e i r b o r e a n d r e l e a s e i t by d i f f u s i o n t h r o u g h t h e a i r l a y e r above t h e agent i n t h e b o r e . A somewhat more c o m p l e x e x a m p l e i s p o r o u s n e t w o r k s i n w h i c h t h e a g e n t i s p h y s i c a l l y imbib'ed i n t o t h e p o r e s a n d r e l e a s e d by d i f f u s i o n t h r o u g h t h e f l u i d w h i c h f i l l s these pores. S t r i c t l y speaking t h i s configuration m i g h t a l s o be t h o u g h t o f a s a m a t r i x d e v i c e . Both of t h e s e e x a m p l e s o r d i n a r i l y may b e e x p e c t e d t o f o l l o w a V"F t y p e r e l e a s e p a t t e r n a l t h o u g h e x t e r n a l f a c t o r s may m o d e r a t e t h e d i f f u s i o n a n d c h a n g e t h e r e l e a s e p r o file. This i s true f o r a l l of the other devices des c r i b e d e a r l i e r , a n d i t i s n o t uncommon f o r t h e e x t e r n a l r e s i s t a n c e s t o make s y s t e m s c o m p o s e d o f d e v i c e s w i t h an i n t r i n s i c VF release p r o f i l e approach "zero order" k i n e t i c s . The a b o v e c o n c e p t s a r e d i s c u s s e d i n one f o r m o r another i n the papers which f o l l o w . There are conc e p t s w h i c h h a v e b e e n o r c o u l d be u s e d t h a t a r e n o t i n c l u d e d i n t h i s b o o k a n d " o s m o t i c pumps" ( 8 , 2 9 ) a r e an i m p o r t a n t e x a m p l e . Role

of the Polymer

As m e n t i o n e d e a r l i e r , one o f t h e o b j e c t i v e s o f t h i s b o o k i s t o f o c u s on t h e f u n c t i o n a n d s e l e c t i o n o f the polymer used i n t h e c o n t r o l l e d r e l e a s e formulation. The r e q u i r e m e n t s o f t h e p o l y m e r a r e o b v i o u s i n some c a s e s b u t i t i s u s e f u l t o s u m m a r i z e h e r e what a f e w o f the c o n s i d e r a t i o n s i n i t s s e l e c t i o n might be: 1.

D i f f u s i o n and s o l u b i l i t y c h a r a c t e r i s t i c s w i t h the a c t i v e or e n v i r o n m e n t a l agents to p r o v i d e the d e s i r e d r e l e a s e c o n t r o l (see e.g. 19,20,21,23,24,31).

2.

C o m p a t i b i l i t y with the environment ( e . g . not toxic or antagonistic i n medical a p p l i c a tions) ·

3.

S t a b i l i t y i n the environment (should degrade o r change u n d e s i r a b l y ) .

4.

Compatibility

with

the a c t i v e

agent

not

(no


10

CONTROLLED

RELEASE POLYMERIC

undesirable actions) .

reactions

or p h y s i c a l

5.

Mechanical

properties,

6.

Ease

7.

Cost,


Testing:

FORMULATIONS

inter-

of f a b r i c a t i o n .

Laboratory

Versus

Field

In d e v e l o p i n g controlled release formulations i t i s i n e v i t a b l y c h e a p e r t o do i n i t i a l t e s t i n g i n a l a b o r a t o r y under c o n t r o l l e d c o n d i t i o n s t h a t match c l o s e l y the a p p l i c a t i o n s i t u a t i o n (In v i t r o i n medical terminology), but u l t i m a t e l y f i e l d t e s t i n g under a c t u a l c i r c u m s t a n c e s ( i n v i v o i n m e d i c a l terminology) i s necessary. In medical a p p l i c a t i o n s i n v i v o u s e may i n v o l v e p l a c i n g t h e d e v i c e i n t h e body by i n s e r t i o n t h r o u g h a body o r i f i c e , i n g e s t i o n , i m p l a n t a t i o n , i n j e c t i o n , o r by a p p l i c a t i o n t o t h e skin. The p a p e r s t h a t f o l l o w d e a l w i t h v a r i o u s s t a g e s o f t e s t i n g a n d i n some c a s e s d i r e c t c o m p a r i s o n s b e t w e e n them a r e made. I t i s u s e f u l t o summar i z e h e r e a few o f t h e f a c t o r s t h a t c o u l d contribute to d i f f e r e n t p e r f o r m a n c e i n t h e f i e l d t h a n t h e laboratory : 1.

E x t e r n a l hydrodynamic boundary l a y e r s . In t h e l a b t h e s e c a n be e x t r e m e l y w e l l c o n t r o l l e d compared t o t h e f i e l d . Frequently i n t h e l a b t h e s e a r e made s m a l l i n t e n t i o n a l ly i n order to study the i n t r i n s i c charact e r i s t i c s of the device. In the f i e l d these e f f e c t s may b e d i f f e r e n t t h a n i n t h e l a b a n d i n f a c t may be v a r i a b l e i n t i m e . The c o n s e q u e n c e s may be d r a m a t i c . F o r example, a m a t r i x d e v i c e may show a V t * r e l e a s e p a t t e r n i n t h e l a b where t h e e x t e r n a l b o u n d a r y l a y e r e f f e c t i s small, but i n the f i e l d a "zero o r d e r " r e l e a s e r a t e c o u l d be o b s e r v e d (28) b e c a u s e t h i s e f f e c t i s l a r g e - and t h i s c o u l d be a d v a n t a g e o u s !

2.

Environmental f a c t o r s not considered i n the lab: w i n d , s u n ( e . g . UV degradation), t e m p e r a t u r e f l u c t u a t i o n s , i n t e r f e r e n c e by e n v i r o n m e n t a l c h e m i c a l s and o r g a n i s m s , e t c .


1.

PAUL Polymers

3.

Fabrication V a r i a b i l i t y , Generally formu l a t i o n s for laboratory testing are made by hand or by proto-type processes whereas f i e l d testing requires scale-up of the pro cess to commercial or near-commercial con ditions. This may produce differences or v a r i a b i l i t i e s not anticipated.


Commercial Products In spite of the r e l a t i v e l y short l i f e of con t r o l l e d release technology, a number of commercial products have already been introduced. The following Table I summarizes a sampling of these products. It is s t i l l too early to know much about what the fate of this technology w i l l be i n the market place, but the next few years should be i n t e r e s t i n g . Several of the papers included here deal with devices which are already commercial or soon w i l l be. As a consequence, some do not delve deeply into the more i n t e r e s t i n g technical d e t a i l s owing to understandable proprietary restraints. Proceedings 1.

2. 3.

L i t e r a t u r e Cited of Major Symposia on Controlled Release

Tanquary, A . C . and Lacey, R.E., E d i t o r s , Con t r o l l e d Release of B i o l o g i c a l l y Active Agents, V o l . 47 of Advances in Experimental Medicine and Biology, Plenum Press, N . Y . , 1974. C a r d a r e l l i , N. F., E d i t o r , Controlled Release Pesticide Symposium, The University of Akron, 1974. H a r r i s , F. W., E d i t o r , Proceedings 1975 Inter national Controlled Release Pesticide Symposium, Wright State U n i v e r s i t y , Dayton, Ohio, 1975. Books and Reviews on Controlled Release

4. 5.

6. 7.

Williams, Α . , Sustained Release Pharmaceuticals, Noyes Development Corp., Park Ridge, N.J., 1969. A l l a n , G. G . , Chopra, C. S . , Friedhoff, J. F., Gara, R. I., Maggi, M. W., Neogi, Α. Ν . , Roberts, S. C., and Wilkens, R. M., "Pesticides, P o l l u t i o n , and Polymers", CHEMTECH (1973), 3, 171-178. Colbert, J . C., Controlled Action Drug Forms, Noyes Data Corp., Park Ridge, N.J., 1974. C a r d a r e l l i , N. F., "Concepts in Controlled Re lease - Emerging Pest Control Technology", CHEMTECH (1975), 5, 482-485.


12


Table Some


Trade

Commercial

Name

I

C o n t r o l l e d Release

Company

FORMULATIONS

Products

Comments

NOFOUL

B. F . Goodrich

A n t i f o u l i n g rubber c o a t i n g . M a t r i x d e v i c e (some v e r s i o n s e m p l o y a membrane in addition)

NO-PEST STRIP

Shell

A matrix device f o r release of i n s e c t i c i d e

HERCON DISPENSER

HealthChem

A l a m i n a t e d membrane d e vice f o rrelease of p e s t i c i d e and o t h e r agents

PRECISE

3M

Microencapsulated fertilizer

OSMOCOAT

Sierra

Microencapsulated fertilizer

PENNCAP-M

Pennwalt

Microencapsulated methyl parathion insecticide

OCCUSERT

Alza

L a m i n a t e d membrane d e v i c e for release of p i l o c a r p i n e i n t h e eye f o r glaucoma control

PROGESTASERT

Alza

A membrane r e s e r v o i r d e v i c e for release of progesterone in the uterus f o r b i r t h control

BioMET

M&T

A matrix device f o r release of a m o l l u s c i c i d e

International C o p p e r Research Association

A matrix device f o r release of a m o l l u s c i c i d e

SRM

INCRACIDE E-51


1.

PAUL

8.

9.

B a k e r , R. W. and L o n s d a l e , Η. Κ . , " C o n t r o l l e d D e l i v e r y - An Emerging Use f o r Membranes", CHEMTECH, (1975),5,668-674. Cardarelli, Ν. F., C o n t r o l l e d R e l e a s e P e s t i c i d e s F o r m u l a t i o n s , CRC P r e s s , C l e v e l a n d , O h i o , 1976. Books and Reviews on


13

Polymers

Microencapsulation

10. Chang, T. M. S., Artificial Cells, C. C. Thomas, Springfield, Ill., 1972. 11. Gutcho, Μ . , Capsule Technology and M i c r o e n c a p s u lation, Noyes Data C o r p . , Park R i d g e , N . J., 1972. 12. Vandegaer, J. Ε., Editor, MicroencapsulationP r o c e s s e s and A p p l i c a t i o n s , Plenum P r e s s , New Y o r k , 1974. 13. F a n g e r , G. O., "What Good Are M i c r o c a p s u l e s " , CHEMTECH, (1974), 4, 397-405. 14. Goodwin, J. T . and S o m e r v i l l e , G. R., " M i c r o e n c a p s u l a t i o n by P h y s i c a l Methods", CHEMTECH, (1974), 4, 623-626. 15. Chang, T . M. S . , "Artificial Cells", CHEMTECH, (1975), 5, 80-85. 16. T h i e s , C., " P h y s i c o c h e m i c a l A s p e c t s of M i c r o e n c a p s u l a t i o n " , P o l y m e r - P l a s t . T e c h n o l . E n g . , (1975), 5(1), 1-22. S e l e c t e d Books and Reviews on

Diffusion

17.

T.

B a r r e , r , R. M., D i f f u s i o n In and Through S o l i d s , Cambridge Univ. P r e s s , London, 1941. 18. J o s t , W . , D i f f u s i o n i n S o l i d s , L i q u i d s , and Gases, Academic P r e s s , Ν. Y., 1960. 19. C r a n k , J. and P a r k , G. S., E d i t o r s , D i f f u s i o n i n P o l y m e r s , Academic P r e s s , Ν. Y., 1968. 20. F l y n n , G. L., Yalkowsky, S. H., and Roseman, J., "Mass T r a n s p o r t Phenomena and Models: T h e o r e t i c a l Concepts", J. P h a r m a c e u t i c a l Sci., (1974), 63, 479-510. 21. H o p f e n b e r g , Η. Β., E d i t o r , P e r m e a b i l i t y of Plastic F i l m s and C o a t i n g s to Gases, V a p o r s , and Liquids, V o l . 6 of Polymer S c i e n c e and Technology Plenum P r e s s , Ν. Υ., 1974. 22. C r a n k , J., The Mathematics of D i f f u s i o n , 2nd Ed., C l a r e n d o n P r e s s , O x f o r d , 1975.


14

CONTROLLED RELEASE POLYMERIC FORMULATIONS

Specific

References

Chemburkar, P . B., " E v a l u a t i o n , C o n t r o l , and P r e d i c t i o n of Drug Diffusion Through Polymeric Membranes", Ph.D. Dissertation, Univ. of Fla., 1967. 24. Neogi, S. Α. Ν., "Polymer Selection for Controlled Release P e s t i c i d e s " , P h . D . Dissertation, Univ. of Washington, 1970. 25. H i g u c h i , T., J. Pharm. Sci., (1961), 50, 874. 26. H i g u c h i , T., J. Pharm. Sci., (1963), 52., 1145. 27. Roseman, T. J., and H i g u c h i , W. I., J. Pharm. Sci., (1970), 59, 353. 28. C h i e n , Y . W., Lambert, Η. J. and G r a n t , D. E., J. Pharm. Sci., (1974), 63, 365 and 515. 29. Theeuwes, F., J. Pharm. Sci., (1975), 64, 1987. 30. P a u l , D. R. and McSpadden, S. K., J. Membrane Sci., (1976), 1, 33. 31. M i c h a e l s , A . S., Wong, P. S. L., P r a t h e r , R . , and Gale, R. M., A.I.Ch.E. J., (1975), 21, 1073. Downloaded by UNIV OF ROCHESTER on June 11, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0033.ch001

23.


Controlled Release Polymeric Formulations - American Chemical

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