Chapter 10
Thermally Reversible Gelation Characteristics Poly(oxyethylene)-Poly(oxypropylene) Block Copolymer in Aqueous Solution After Exposure to High-Energy Irradiation
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D. Attwood, C. J. Tait, and J. H. Collett Department of Pharmacy, University of Manchester, Manchester M13 9PL, United Kingdom
γ-irradiation affects the micellar properties and gelation characteristics of the poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymer, Pluronic F127, in aqueous solution. Irradiation caused a progressive increase of hydration of the poly(oxyethyl ene) chains of the poloxamer micelles in solutions at 40° C but no change in the number of monomers per micelle. Exposure to irradiation induced gelation of the poloxamer solutions at a lower concentration than in nonirradiated systems. Increase of temperature of irradiated solutions over the range 25-40° C caused an increase of aggregation number and a concomitant decrease of micellar hydration. In concentrated solutions such changes resulted in the formation of thermally reversible gels. The p o l y ( o x y e t h y l e n e ) - p o l y ( o x y p r o p y l e n e ) ABA b l o c k copolymer, ( p o l oxamer) P l u r o n i c F127, has been t h e s u b j e c t o f r e c e n t i n v e s t i g a t i o n s c e n t e r i n g on i t s p o t e n t i a l use i n t h e c o n t r o l l e d r e l e a s e o f d r u g s . S o l u t i o n s o f t h i s poloxamer w i t h c o n c e n t r a t i o n s g r e a t e r t h a n about 20% a r e r e v e r s i b l y t r a n s f o r m e d from low v i s c o s i t y t r a n s p a r e n t sol u t i o n s t o g e l s on warming t o body t e m p e r a t u r e . P r e v i o u s s t u d i e s have e s t a b l i s h e d t h e p r e s e n c e o f m i c e l l e s i n d i l u t e s o l u t i o n (_0 and i t now seems l i k e l y t h a t g e l a t i o n i s a r e s u l t o f i n t e r a c t i o n s between t h e p o l y ( o x y e t h y l e n e ) c h a i n s o f a d j a c e n t m i c e l l e s i n c o n c e n t r a t e d aqueous solutions. These i n t e r a c t i o n s become e f f e c t i v e i n l i n k i n g t o g e t h e r the m i c e l l a r u n i t s due t o a temperature i n d u c e d l o s s o f t h e h y d r a t i n g water a s s o c i a t e d w i t h the c h a i n s ( 2 - 4 ) . The g e l s have been shown by x - r a y d i f f r a c t i o n , t h e r m a l p o l a r i z i n g m i c r o s c o p y and d i f f e r e n t i a l s c a n n i n g c a l o r i m e t r y t o be c o n s t r u c t e d from a c u b i c a r r a y o f m i c e l l a r subunits ( 5 ) . I t i s i m p l i c i t i n t h e use o f p a r e n t e r a l p r o d u c t s t h a t a s t e r i l e preparation i s required. S e v e r a l methods o f s t e r i l i z a t i o n c a n be used i n c l u d i n g γ-irradiation. However, t h e i n f l u e n c e o f γ-irradiation on the p h y s i c o - c h e m i c a l p r o p e r t i e s o f t h i s poloxamer a r e n o t known. The work o f S t a f f o r d (6) has shown t h a t i n t h e absence o f oxygen, aqueous 0097-6156/87/0348-0128S06.00/0 © 1987 American Chemical Society
Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.
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s o l u t i o n s o f p o l y ( o x y e t h y l e n e ) g l y c o l s c r o s s - l i n k t o form g e l s a f t e r γ-irradiation, p r o v i d e d t h a t the c o n c e n t r a t i o n o f the polymer i s above a c e r t a i n c r i t i c a l c o n c e n t r a t i o n . The i n v e s t i g a t i o n s o f A l Saden and coworkers (7-8) have shown t h a t t h e r e i s a minimum c h a i n l e n g t h r e q u i r e m e n t o f about 50 e t h y l e n e o x i d e u n i t s p e r h y d r o p h i l i c c h a i n which must be exceeded i f s c i s s i o n o f the p o l y ( o x y e t h y l e n e ) c h a i n s i s t o be a v o i d e d . These workers s u c c e s s f u l l y i n d u c e d the g e l a t i o n o f s o l u t i o n s o f P l u r o n i c s F68, F87 and F88 by exposure t o γ-irradiation. I n t h i s p r e s e n t study we r e p o r t the e f f e c t o f graded doses o f γ-irradiation on the p r o p e r t i e s o f the m i c e l l e s o f P l u r o n i c F127 and on the temperature i n d u c e d m i c e l l a r changes which l e a d t o the eventual g e l a t i o n of these s o l u t i o n s . I n view o f the b a t c h v a r i a b i l i t y o f the m i c e l l a r p r o p e r t i e s o f poloxamers (3) comparisons have been made w i t h s o l u t i o n s o f the same b a t c h which have not been subjected to i r r a d i a t i o n . M a t e r i a l s and Methods Materials. P l u r o n i c F127 was a g i f t from P e c h i n e y Ugine Kuhlmann and was used as r e c e i v e d . P l u r o n i c F127 i s an ABA p o l y ( o x y e t h y l e n e ) p o l y ( o x y p r o p y l e n e ) - p o l y ( o x y e t h y l e n e ) b l o c k copolymer c o n t a i n i n g app r o x i m a t e l y 70% o x y e t h y l e n e w i t h a nominal m o l e c u l a r weight o f 1.15 χ 10*. W
I r r a d i a t i o n Procedure. 30% /w s o l u t i o n s o f poloxamer were p r e p a r e d i n d i s t i l l e d water by the c o l d p r o c e s s and s a t u r a t e d w i t h n i t r o u s oxide. T h i s agent i s a known scavenger o f h y d r a t e d e l e c t r o n s and i s known t o enhance c r o s s l i n k i n g o f p o l y ( o x y e t h y l e n e ) c h a i n s ( 9 ) . V i a l s c o n t a i n i n g t h e s e s o l u t i o n s were i r r a d i a t e d a t ambient temperature i n a 2000 C i C o s o u r c e a t a dose r a t e o f 0.5 Mrad h ~ Physicoc h e m i c a l measurements were performed on s o l u t i o n s p r e p a r e d by d i l u t i o n o f t h e s e i r r a d i a t e d samples. 6 0
1
L i g h t S c a t t e r i n g Measurements. T o t a l i n t e n s i t y l i g h t s c a t t e r i n g measurements were c a r r i e d out u s i n g a F i c a 42000 p h o t o g o n i o d i f f u s o meter a t a wavelength of 546 nm. S o l u t i o n s of poloxamer were c l a r i f i e d by u l t r a f i l t r a t i o n t h r o u g h 0.22 urn M i l l i p o r e f i l t e r s . Temperature c o n t r o l was ± 0.1° C. The r e f r a c t i v e i n d e x i n c r e m e n t s were measured by d i f f e r e n t i a l r e f r a c t o m e t r y a t 546 nm.
Q u a s i - e l a s t i c l i g h t s c a t t e r i n g measurements were performed u s i n g a M a l v e r n K7027 c o r r e l a t o r w i t h 26 d e l a y c h a n n e l s a r r a n g e d i n g e o m e t r i c p r o g r e s s i o n , i n c o n j u n c t i o n w i t h a 2W Argon i o n l a s e r a t 488 nm. A l l measurements were a t an a n g l e o f 90° t o the i n c i d e n t beam. S o l u t i o n s were c l a r i f i e d by u l t r a f i l t r a t i o n as d e s c r i b e d above. Temperature c o n t r o l was ± 0.1° C. V i s c o s i t y Measurements, P r e v i o u s s t u d i e s (2) have shown t h a t d i l u t e s o l u t i o n s o f P l u r o n i c F127 e x h i b i t Newtonian f l o w c h a r a c t e r i s t i c s and c o n s e q u e n t l y , i t i s p e r m i s s i b l e t h a t the v i s c o s i t y o f t h e s e s o l u t i o n s i s measured by c a p i l l a r y v i s c o m e t r y . A suspended-level v i s c o m e t e r was used and s o l u t i o n s were t h e r m o s t a t t e d to w i t h i n
Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.
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± 0.001°. P a r t i a l s p e c i f i c volumes were c a l c u l a t e d from d e n s i t y measurements on poloxamer s o l u t i o n s made u s i n g a d i g i t a l d e n s i t y meter (Paar DMA 0 2 C ) .
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Results
and D i s c u s s i o n
E f f e c t o f R a d i a t i o n Dose on M i c e l l a r P r o p e r t i e s . F i g u r e 1 shows t h e c o n c e n t r a t i o n dependence o f t h e m i c e l l a r d i f f u s i o n c o e f f i c i e n t a t 40° as d e t e r m i n e d by q u a s i - e l a s t i c l i g h t s c a t t e r i n g (QELS) f o r s o l u t i o n s s u b j e c t e d t o r a d i a t i o n doses o f up t o 4.56 Mrad. L i m i t i n g d i f f u s i o n c o e f f i c i e n t s , D ,were o b t a i n e d by e x t r a p o l a t i o n o f d a t a f o r d i l u t e s o l u t i o n s (
