Controlled Release from Ultramicroporous Cellulose Triacetate - ACS

26 Controlled Release from Ultramicroporous Cellulose

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on September 4, 2017 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0033.ch026

Triacetate A. S. OBERMAYER and L. D. NICHOLS Moleculon Research Corp., 139 Main St., Cambridge, Mass. 02142

A broad range o f c o n t r o l l e d r e l e a s e i n v e s t i g a t i o n s have been c a r r i e d out r e c e n t l y based on the unique p r o p e r t i e s of an ultramicroporous, open-celled form of cellulose triacetate which has the t r a d e name POROPLASTIC® when i n film o r membrane form and SUSTRELLE when in microbeador powder form f o r c o n t r o lled r e l e a s e . Since this product as formed normally contains between 70% and 98% liquid, it is often r e f e r r e d t o as "a solid composed mostly o f liquid" o r as a "molecular sponge." I t is made by a coagulation process which r e s u l t s i n a crystalline, non-crosslinked polymer matrix. For some a p p l i c a t i o n s , t h e p r o p e r t i e s o f P o r o p l a s t i c a r e comparable t o a typical membrane, sometimes it is considered similar to a hydrogel, a n d s o m e t i m e s it responds more l i k e a porous polymer o r plastisol. S u s t r e l l e powder is u s u a l l y compared t o a microencapsulated product o r an absorbent. However, none of these other m a t e r i a l s have the same unique combination o f p r o p e r t i e s . Experiments which have been performed on P o r o p l a s t i c film and Sustrelle powder have, thus far, shown no d i f f e r e n c e i n p r o p e r t i e s t h a t c o u l d n o t be a c c o u n t e d f o r s o l e l y by t h e d i f f e r e n c e i n surface area-to-volume r a t i o between f i l m and powder. In almost al I cases, i n i t i a l laboratory i n v e s t i g a t i o n s are best c a r r i e d out with t h e product in f i l m form, because ( I ) f i l m samples have w e l l defined dimensions and i n t e r n a l loading c a p a c i t i e s ; (2) they can e a s i l y be handled and weighed; (3) phase changes and shrinkage can be v i s u a l l y observed i n t h e t r a n s p a r e n t f i l m ; (4) excess s u r f a c e l i q u i d c a n r e a d i l y be removed by b l o t t i n g ; and (5) experience gained with f i l m can be roughly t r a n s l a t e d i n t o subsequent experiments with powder. Any l i q u i d (as long as i t i s not a s o l v e n t f o r c e l l u l o s e t r i a c e t a t e ) c a n be impregnated i n t o S u s t r e l l e o r P o r o p l a s t i c by a simple d i f f u s i o n a l exchange process of m i s c i b l e l i q u i d s . The most common I iquî d imprégnants are aqueous so I ut ions, a Icohols, a l c o h o l i c s o l u t i o n s , e s s e n t i a l o i l s , al i p h a t i c o r aromatic hydrocarbons, s i l i c o n e o i l s , e s t e r s , ketones, and l i q u i d monomers. Table I provides a comparison of mechanical p r o p e r t i e s as a f u n c t i o n of content for water and mineral o i l f i l l e d m a t e r i a l . TM

303

Paul and Harris; Controlled Release Polymeric Formulations ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

304

CONTROLLED

TABLE

PROPERTIES

Composition — Resin % Water % Mineral O i l % Apparent Pore S i z e , Angstroms Specific Gravity Tensile Strength, p s i Elongation a t Break, % Tensile Strength a f t e r Drying, p s i E l a s t i c Modulus, p s i Elongation a t E l a s t i c Limit, %

FORMULATIONS

I

POROPLASTIC

Aqueous MA-70

Property


OF

RELEASE POLYMERIC

FILM

Oi 1 MA-70

Aqueous MA-92

Oi 1 MA-92

8

30

—

—

—

70

92

14

60

14

60

1.09 1,300 44

1.02 175 20

1.01 2,300 41

0.91 400 32

2,600

550

21,000

200

41,000

3,400

2.4

4.0

2.4

3.1

8 92

30 70

—

H y d r a u l i c f l u x data indicates t h a t P o r o p l a s t i c f i l m a c t s as a homogeneous membrane whose f l u x v a r i e s l i n e a r l y w i t h p r e s s u r e and i n v e r s e l y w i t h f i l m t h i c k n e s s . The c h a r a c t e r i s t i c p o r e s i z e o f e i t h e r f i l m o r powder c a n be v a r i e d by c o n t r o l o f t h e l i q u i d content o f t h e product. Measurements o f c h a r a c t e r i s t i c pore d i a m e t e r have been made by d e t e r m i n i n g t h e a b i l i t y o f f i l m t o a c t as a f i I t e r and r e t a i n m o l e c u l e s o f w e l l - d e f i n e d d i m e n s i o n s . Table II and F i g u r e I d e m o n s t r a t e t h e v a r i a t i o n i n c h a r a c t e r i s t i c p o r e dimensions with t h e water content o f t h e f i l m .

ΙΟ

3

ΙΟ ΙΟ MOLECULAR WEIGHT O F S O L U T E 4

5

I0

6

Figure 1. Effect of water content on molecular weight cutoff (90% retention, 0.004-in. film)


26.

OBERMAYER A N D NICHOLS

Ultramicwporous

Cellulose

Triacetate

305

TABLE II


RETENTION CHARACTERISTICS OF POROPLASTIC FILM

Molecular Weight

Solute Phenyl-Alanine Sucrose V i t a m i n B-12 Inulin Cytochrome C Beta L a c t o g l o b u l i n HemogIob i η Albumin (Bovine) Gamma G l o b u l i n Apoferritin B l u e D e x t r a n 2000

165 342 1,355 5,200 12,400 35,000 64,000 67,000 153,000 480,000 2,000,000

Apparent Pore Diameter in Angstroms Apparent Pore Diameter in Microns Water C o n t e n t by W e i g h t

1.8

1

1-2

*1

1.0

97 95 >99 >99 >99

25 >98 >99 >99

14

25

60

>200

0.0014

0.0025

0.006

>0.02

92%

91.5%

—

1

— —

—

85%

I

0.5 Hour Half life, X^-Departure from Zero V Order at 0.5 Hours

85% Water

1.41

I

>99 >99 >99 >99 >99 >99 >99

0 0 0 0 0 0 0 0 0 42 93

0 0 0 0 7

0 0 0 10 87

0 0 70

10%

1

1.6

% R e t e n t i o n a t 30 p s ion 4 mi 1 FÎ 1ms MA-92 MA-97.5 MA-85 MA-70

—

-

£ 0.8 UJ r?, 0.6 * 0.4

42% Water

yZO

Hour Half life

\ ^

Departure from Z e r o ^ ^ O v Order at 5.3 Hours \ Λ

1 20

I

I

40 60 PERCENT RELEASED

I 80

Ν 100

Figure 2. Release of precipitated zinc fluorescein from MA-85 (85% water) poroplastic film and from a simihr sample dried to 42% water



306

CONTROLLED RELEASE POLYMERIC FORMULATIONS

In c o n t r a d i s t i n c t i o n t o most g e l s , P o r o p l a s t i c and S u s t r e l l e s h r i n k i r r e v e r s i b l y when l i q u i d i s removed f r o m them, f o r e x a m p l e , by e v a p o r a t i o n . T h i s r e s u l t o c c u r s b e c a u s e i t i s n o t c r o s s l i n k e d and, t h e r e f o r e , i s no more s t a b l e i n i t s s w o l l e n s t a t e t h a n a f t e r i t h a s been d r i e d . When a n i n t e r n a l l i q u i d s u c h a s w a t e r i s p a r t i a l l y o r w h o l l y removed, s h r i n k a g e a p p e a r s t o o c c u r i n i t i a l l y w i t h t h e c o l l a p s e o f t h e s m a l l e s t p o r e s and e v e n t u a l l y a l s o i n c l u d e s t h e l a r g e r pores. Thus, l i q u i d s o r s o l u t i o n s can i n i t i a l l y be d i f f u s e d i n t o t h e u l t r a m i c r o p o r o u s m a t r i x . S u b s e q u e n t l y , by a d r y i n g p r o c e s s t h e p o r e s c a n be p a r t i a l l y c o l l a p s e d s o a s t o reduce t h e r a t e o f a c t i v e agent d i f f u s i o n t o t h e s u r f a c e o f t h e matrix. T h i s p o r e c o l l a p s e p r o c e s s r e p r e s e n t s t h e most common method o f f i x a t i o n o r r e d u c i n g t h e r a t e o f r e l e a s e o f a c t i v e agent. In g e n e r a l , a t h r e e s t e p p r o c e s s i s i n v o l v e d i n t h e c o n t r o l led r e l e a s e o f a c t i v e a g e n t . The s t e p s a r e : ( I ) i m p r e g n a t i o n , ( 2 ) f i x a t i o n , and ( 3 ) d i f f u s i o n a l r e l e a s e . The i m p r e g n a t i o n s t e p n o r mal I y i n v o l v e s a s e r i e s o f d i f f u s i o n a l e x c h a n g e s o f m i s c i b l e l i q u i d s u n t i l t h e l i q u i d w i t h i n t h e polymer m a t r i x i s t h e a c t i v e a g e n t o r a s o l u t i o n o f t h e a c t i v e a g e n t t o be r e l e a s e d . The f i x a t i o n s t e p u t i l i z e s some p r o c e d u r e t o r e t a r d t h e r a t e o f d i f f u s i o n o f a c t i v e a g e n t t o t h e environment. In a d d i t i o n t o t h e p o r e c o l l a p s e f i x a t i o n method d e s c r i b e d a b o v e , t h e r e a r e a number o f f i x a t i o n methods b a s e d on t h e p r e c i p i t a t i o n o f a c t i v e a g e n t w i t h i n t h e porous m a t r i x . F o r e x a m p l e , when t h e p o r o u s m a t r i x i s impregnated w i t h a s a t u r a t e d s o l u t i o n , e v a p o r a t i o n o f t h e s o l v e n t can c a u s e t h e s o l u t e t o p r e c i p i t a t e w i t h i n t h e p o r o u s m a t r i x . The s o l v e n t e v a p o r a t i o n c a u s e s p a r t i a l p o r e c o l l a p s e , and t h e p r e c i p itated a c t i v e a g e n t f i l l s t h e remaining pore s t r u c t u r e a n d prevents complete c o l l a p s e . I n t e r n a l p r e c i p i t a t i o n o f an a c t i v e a g e n t c a n a l s o be a c c o m p l i s h e d b y a s o l v e n t s u b s t i t u t i o n method. In t h i s c a s e , a f t e r i m p r e g n a t i o n w i t h a s o l u t i o n o f t h e a c t i v e a g e n t , a n o t h e r l i q u i d i s added w i t h w h i c h t h e o r i g i n a l s o l v e n t i s m i s c i b l e b u t i n w h i c h t h e a c t i v e agent i s i n s o l u b l e . A t h i r d p r e c i p i t a t i o n technique i η vo I ves c h e m i c a l r e a c t i o n within the porous m a t r i x t o produce a p r e c i p i t a t e . D i f f u s i o n a l r e l e a s e may r e q u i r e a t r i g g e r mechanism f o r initiation. I t d i f f e r s f r o m m i c r o e n c a p s u l a t i o n i n t h a t no o u t e r s h e l l i s b r o k e n , and i t d i f f e r s f r o m common a d s o r b e n t s s u c h a s a c t i v a t e d c a r b o n i n t h a t no c h e m i c a l b o n d i n g t o t h e s u b s t r a t e i s involved. A s p e c i f i c example which demonstrates t h e s t e p s i n v o l v e d i n t h i s p r o c e s s i s t h e c o n t r o l I ed r e l e a s e o f f l u o r e s c e i n f r o m a MA-85 Poroplastic f i l m matrix. Sodium f l u o r e s c e i n i s v e r y s o l u b l e ( o v e r 20%) i n w a t e r , w h e r e a s , z i n c f l u o r e s c e i n i s r e p o r t e d t o be s o l u b l e o n l y t o t h e e x t e n t o f a b o u t 0.\6%. When a 5% aqueous s o l u t i o n o f s o d i u m f l u o r e s c e i n i s a l l o w e d t o d i f f u s e i n t o a 0.009 i n c h w a t e r c o n t a i n i n g f i l m f r o m one s i d e and a 0.5% aqueous s o l u t i o n o f z i n c c h l o r i d e i s a l l o w e d t o d i f f u s e i n t o t h e f i l m from t h e o t h e r s i d e , an i n t e r n a l p r e c i p i t a t e o f z i n c f l u o r e s c e i n o c c u r s c l o s e t o t h e middle of the P o r o p l a s t i c f i l m . The p r e c i p i t a t e c a n be o b s e r v e d



26.

OBERMAYER AND NICHOLS

Ultramicroporous

Cellulose

Triacetate

307

i n t h e t r a n s p a r e n t f i l m by t h e o n s e t o f c l o u d i n e s s and e v e n t u a l l y t h e f i l m may become d i s t e n d e d o r b r i t t l e a s l a r g e amounts o f z i n c f l u o r e s c e i n p r e c i p i t a t e a r e formed n e a r t h e c e n t e r o f t h e f i l m . In o r d e r t o i n s u r e t h a t o n l y t h e s l i g h t l y s o l u b l e z i n c f l u o r e s c e i n i s p r e s e n t w i t h i n t h e f i l m , a f i n a l w a t e r wash i s c a r r i e d o u t t o remove e x c e s s s o d i u m f l u o r e s c e i n . A f i l m s a m p l e s o p r e p a r e d was t h e n p l a c e d i n w e l l a g i t a t e d w a t e r and t h e r a t e o f r e l e a s e o f z i n c f l u o r e s c e i n was measured. An a l m o s t c o n s t a n t o r z e r o o r d e r r e l e a s e was o b s e r v e d f o r 30 m i n u t e s r e p r e s e n t i n g 50% o f t h e loaded m a t e r i a I. T h i s was f o l l o w e d by a d e c l i n i n g r e l e a s e r a t e g i v i n g 90% d e l i v e r y a f t e r two hours. A second p i e c e o f z i n c f l u o r e s c e i n f i l m prepared as above was d r i e d f r o m 85% w a t e r t o 42.5% w a t e r and showed a c o n s t a n t r e l e a s e r a t e f o r o v e r 5 h o u r s , r e p r e s e n t i n g more t h a n 80$ o f t h e c o n t a i n e d l o a d i n g . R a t e d a t a f o r b o t h f i l m s a m p l e s a r e shown in F i g u r e 2. T h i s t y p e o f e x p e r i m e n t h a s been e x t e n d e d t o c a p s u l e f o r m s . P o r o p l a s t i c f i l m c a n be f a b r i c a t e d i n t o t h e shape and a p p e a r a n c e of a t y p i c a l 2-piece hard g e l a t i n c a p s u l e . Zinc fluorescein, or o t h e r a c t i v e a g e n t s , c a n be p l a c e d d i r e c t l y w i t h i n t h e c a p s u l e , and t h e r a t e o f r e l e a s e c a n be measured t h r o u g h t h e p e r m e a b l e wa I I s of t h e c a p s u l e . Since t h e r a t e determining step i s d i f f u s i o n t h r o u g h t h e c a p s u l e w a l l s and t h e r e i s a l a r g e r e s e r v o i r o f s o l i d a c t i v e agent t o maintain a s a t u r a t i o n level w i t h i n t h e c a p s u l e , c o n s t a n t r e l e a s e r a t e s a r e commonly m e a s u r e d . Such e x p e r i m e n t s have been c a r r i e d o u t n o t o n l y w i t h z i n c f l u o r e s c e i n b u t a l s o w i t h such d i v e r s e compounds a s m e t h y l e n e b l u e and p o t a s s i u m c h l o r i d e . M e t h y l e n e b l u e i s a b o u t 3% w a t e r s o l u b l e , and p o t a s s i u m c h l o r i d e i s a b o u t 30% w a t e r s o l u b l e . From an e x p e r i m e n t a l s t a n d p o i n t , t h e p r i n c i p a l c o m p l i c a t i n g f e a t u r e i s t h e need f o r t h e c a p s u l e t o w i t h s t a n d an o s m o t i c p r e s s u r e b u i l d up, o r a l t e r n a t i v e l y o n e c a n b a l a n c e t h e i o n i c s t r e n g t h and r e s u l t a n t o s m o t i c p r e s s u r e s on b o t h sides of the capsule w a l l . When s o l u b i l i t i e s a r e below \%, t h e s e o s m o t i c p r e s s u r e s g e n e r a l l y c a n be i g n o r e d . P o r o p l a s t i c capsules a l s o o f f e r a convenient form f o r c a r r y i n g o u t l a b o r a t o r y e x p e r i ments and r e l e a s i n g a c t i v e a g e n t s a t a c o n s t a n t r a t e . We a n t i c i p a t e t h a t many new a p p l i c a t i o n s f o r P o r o p l a s t i c c a p s u l e s w i l l be f o u n d . T h e r e a r e many o t h e r s i m i l a r t y p e s o f e x p e r i m e n t s t h a t c a n be p e r f o r m e d w i t h a c t i v e a g e n t s t h a t have p r a c t i c a l u t i l i t y a s pharmaceuticals, cosmetics, a i r f r e s h e n e r s , t o i l e t r i e s , household p r o d u c t s and p e s t i c i d e s .


Controlled Release from Ultramicroporous Cellulose Triacetate - ACS

Recommend Documents