Release and Delayed Release of Water-Soluble Drugs from Polymer

medium water solubility (= 2%) , but had the shortcoming of relatively ... Ethanol and water swelling (% Eth, % H2 0) as well as drug- ..... 150. CONT...
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Chapter 11

Release and Delayed Release of Water-Soluble Drugs from Polymer Beads with Low Water Swelling Karl F. Mueller

Downloaded by GEORGETOWN UNIV on June 26, 2016 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch011

Ciba-Geigy Corporation, Ardsley, NY 10502

Highly water soluble drugs, as they are typical for oral administration, can be released from polymer beads with low (< 10%) water- but high ethanolswelling capacity at controlled rates, for up to 8 hours. The release of oxprenolol-HCl (77% water solubility) and diclofenac Na (2.6% water solubility) from drug loaded monoliths is a function of water content and crosslink density. By partial extraction of the drug loaded beads the release can be further slowed down and, in the case of oxprenolol-HCl, delayed for several hours; the delay is dependent on water content of the polymer and is the result of the formation of a hydrophobic surface membrane.

H y d r o g e l beads have f i r s t been proposed by 0. W i c h t e r l e (1) as drug c a r r i e r s i n o r a l drug d e l i v e r y . They make an a t t r a c t i v e m u l t i p a r t i c u l a t e o r a l dosage form because they c a n e a s i l y be s y n t h e s i z e d , have good b i o c o m p a t i b i l i t y and p r o v i d e v e r y r e p r o d u c i b l e , d i f f u s i o n controlled release. However, t h e r e l e a s e o f l a r g e doses o f h i g h l y water s o l u b l e drugs - c o n d i t i o n s c h a r a c t e r i s t i c f o r o r a l d e l i v e r y from t y p i c a l h y d r o g e l s such a s p o l y - 2 - h y d r o x y e t h y l m e t h a c r y l a t e i s g e n e r a l l y t o o f a s t and t h e r e f o r e l i m i t s t h e u s e f u l n e s s o f such h y d r o g e l beads t o drugs w i t h low water s o l u b i l i t y o r s m a l l dosages. To a c e r t a i n e x t e n t t h e r e l e a s e c a n be slowed down by i n c r e a s i n g t h e bead s i z e ; a d o u b l i n g o f bead d i a m e t e r i n c r e a s e s t h e h a l f l i f e f o r r e l e a s e about t h r e e f o l d . But even beads w i t h d i a m e t e r s as l a r g e as 1.0-1.5 mm, which i s t h e upper p r a c t i c a l s i z e l i m i t f o r s u s p e n s i o n polymeri z a t i o n , a r e n o t l a r g e enough t o g i v e p r a c t i c a l r e l e a s e r a t e s f o r v e r y water s o l u b l e d r u g s . Previous attempts to reduce r e l e a s e r a t e s i n c l u d e t h e s y n t h e s i s o f membrane c o v e r e d and o f g r a d i e n t - b e a d s by d i f f u s i o n c o n t r o l l e d i n t e r f a c i a l p o l y c o n d e n s a t i o n and g r a f t i n g ( 2 ) . Here t h e membranes d e l a y t h e r e l e a s e by s l o w i n g down i n i t i a l water a b s o r p t i o n , whereas t h e c o m p o s i t i o n a l g r a d i e n t s r e s u l t i n a c o r r e s ponding drug d i s t r i b u t i o n g r a d i e n t a f t e r drug l o a d i n g and t h e r e f o r e g i v e p e r i o d s o f almost c o n s t a n t r e l e a s e , a l t h o u g h a t t h e expense o f total drug-loading.

0097-6156/87/0348-0139506.00/0 €> 1987 American Chemical Society

Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Downloaded by GEORGETOWN UNIV on June 26, 2016 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch011

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CONTROLLED-RELEASE TECHNOLOGY

The i n i t i a l r a t e of drug r e l e a s e from polymer m o n o l i t h s can be slowed down by s u r f a c e e x t r a c t i o n and s e v e r a l such methods have been described (3,4). A c o n t r o l l e d s u r f a c e - e x t r a c t i o n p r o c e s s l e a d i n g to a s i g m o i d a l d r u g d i s t r i b u t i o n and t h e r e b y a c h i e v i n g n e a r l y c o n s t a n t r e l e a s e of v e r y water s o l u b l e drugs has been d e s c r i b e d by Lee (5, 6, 7). P h a s e - s e p a r a t e d h y d r o g e l c o m p o s i t i o n s w i t h water s w e l l i n g below 25% (8) were found to g i v e p r a c t i c a l r e l e a s e r a t e s f o r drugs w i t h medium water s o l u b i l i t y (= 2%) , but had the s h o r t c o m i n g of r e l a t i v e l y low s w e l l i n g i n o r g a n i c s o l v e n t s . S i n c e d u r i n g the c y c l e of d r u g l o a d i n g and drug r e l e a s e the l o a d i n g s t e p and the a t t a i n a b l e l o a d i n g l e v e l depends on the polymer's degree of s w e l l i n g i n the l o a d i n g s o l v e n t - u s u a l l y a lower a l c o h o l - whereas the r e l e a s e depends i n v e r s e l y on the water u p t a k e , we d e c i d e d to p r e p a r e beads which combined a h i g h e t h a n o l s w e l l i n g c a p a c i t y and t h e r e f o r e h i g h d r u g l o a d a b i l i t y w i t h a w a t e r - s w e l l i n g c a p a c i t y as low as p r a c t i c a l . In t h i s paper we d e s c r i b e the s y n t h e s i s and b e h a v i o r of such beads as c a r r i e r s f o r v e r y water s o l u b l e d r u g s . Experimental Materials. A l l monomers used f o r s y n t h e s i s were f r e e of i n h i b i t o r s and f r e s h l y d i s t i l l e d : 2 - h y d r o x y e t h y l m e t h a c r y l a t e (HEMA); d i m e t h y l a c r y l a m i d e (DMA); N - v i n y l p y r r o l i d o n e (NPV); m e t h y l m e t h a c r y l a t e (MMA); 2 - e t h y l h e x y l a c r y l a t e (ERA); i s o p r o p y l m e t h a c r y l a t e (IPMA); n - b u t y l a c r y l a t e (BA); e t h y l e n e g l y c o l - d i m e t h a c r y l a t e (EGDMA); d i m e t h a c r y l a t e macromer o b t a i n e d by r e a c t i o n of 1 mol p o l y t e t r a r a e t h y l e n e o x i d e d i o l (MW: 2000) w i t h 2 mol 2 , 4 , 4 - t r i m e t h y l - l , 6 - d i i s o c y a n a t o h e x a n e and 2 mol HEMA (PX). A c t i v e i n g r e d i e n t s : O x p r e n o l o l - H C l ; (OX) MW 290; MP: 107°C; 77% s o l u b l e i n water. Diclofenac-Na (DCL); MW: 323; MP: 268°C; 2.65% s o l u b l e i n water a t 25°C; b o t h s u p p l i e d by CIBA-GEIGY. Methods : The polymer beads were s y n t h e s i z e d by s u s p e n s i o n polymer­ i z a t i o n i n c o n c e n t r a t e d aqueous NaCl s o l u t i o n u s i n g 0.1% (of mono­ mers) AIBN as i n i t i a t o r , a monomer/aqueous phase r a t i o of 2/5 and f r e s h l y p r e c i p i t a t e d M g ( 0 H ) as s u s p e n d i n g agent ( 9 ) . The beads were S o x h l e t e x t r a c t e d w i t h e t h a n o l f o r 24 hours and a f t e r d r y i n g c l a s s i f i e d i n t o mesh s i z e s . The 30 mesh (0.59-0.70 mm φ ) and 18 mesh (1.00-1.19 mm φ ) f r a c t i o n s were used f o r r e l e a s e e x p e r i m e n t s (30 mesh f o r DC1; 18 mesh f o r OX). 2

40% m e t h a n o l i c s o l u t i o n s of DC1 and OX were used to l o a d beads to e q u i l i b r i u m , f o l l o w e d by f i l t r a t i o n , r i n s e and d r y i n g v a c u o . Drug c o n c e n t r a t i o n was determined g r a v i m e t r i c a l l y and t o t a l methanol e x t r a c t i o n u s i n g an U V - s p e c t r o p h o t o m e t e r . Drug l e a s e was measured a t 37.5°C i n b u f f e r e d s a l i n e s o l u t i o n (pH = c i r c u l a t i n g through an UV-spectrophotometer c e l l .

the in by re­ 7)

F o l l o w i n g the p r o c e s s d e s c r i b e d i n r e f e r e n c e s 5,6 and 7 ex­ t r a c t i o n was done a t ambient temperature w i t h d i s t i l l e d water or a c e t o n e by s t i r r i n g the m o n o l i t h i c a l l y l o a d e d beads i n e x c e s s s o l ­ v e n t f o r a g i v e n time, f o l l o w e d by f i l t r a t i o n and f r e e z e - d r y i n g . O p t i c a l m i c r o s c o p y to o b s e r v e volume changes was done w i t h a Z e i s s s t e r e o m i c r o s c o p e , u s i n g a 3 mm h i g h round sample c e l l . E t h a n o l and water s w e l l i n g (% E t h , % H 0) as w e l l as d r u g 2

Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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l o a d i n g a r e e x p r e s s e d as weight p e r c e n t o f s w o l l e n o r drug l o a d e d polymer. The polymer c o m p o s i t i o n s , t h e i r r e l e v a n t p h y s i c a l p r o p e r t i e s , t h e i r l o a d i n g s w i t h DC1 and OX t o g e t h e r w i t h t (time t o 50% r e l e a s e ) a r e shown i n T a b l e I . 5

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In s e p a r a t e experiments we had determined t h a t m o d i f i c a t i o n o f a c r y l i c h y d r o g e l c o m p o s i t i o n s based on HEMA o r DMA w i t h a l k y l a c r y l a t e s and t o a l e s s e r e x t e n t , m e t h a c r y l a t e s w i t h from f o u r t o ten c a r b o n atoms i n the e s t e r group r e s u l t s not o n l y i n lower w a t e r , but s h a r p l y i n c r e a s e d e t h a n o l s w e l l i n g f o r a g i v e n c r o s s l i n k d e n s i t y and h y d r o p h o b i c comonomer c o n t e n t ( 1 0 ) . The maximum degree o f s w e l l i n g i s u s u a l l y 5 t o 10% h i g h e r than e t h a n o l s w e l l i n g and o c c u r s i n e t h a n o l - w a t e r m i x t u r e s w i t h ^ 10% w a t e r , c o r r e s p o n d i n g t o a s o l u b i l i t y parameter o n l y s l i g h t l y h i g h e r than t h a t o f e t h a n o l . As shown i n T a b l e I , the comonomer EHA d i s p r o p o r t i o n a l l y r e d u c e s the water c o n t e n t o f 21% and 10% HEMA copolymers No. 9 and 10, p r o b a b l y by s h i e l d i n g the OH-groups from water i n t e r a c t i o n s ; i n c o n t r a s t , the water c o n t e n t o f the 10% HEMA/89% MMA copolymer No. 13 i s , as e x p e c t e d , c l o s e t o one t e n t h t h a t o f poly-HEMA ( T a b l e I , P o l . 3 ) . We chose EHA f o r i t s h i g h h y d r o p h o b i c i t y as main h y d r o p h o b i c comonomer, and MMA t o g e t h e r w i t h 1% EGDMA c r o s s l i n k e r as components to p r e v e n t a g l o m e r a t i o n d u r i n g s u s p e n s i o n p o l y m e r i z a t i o n and t o r e d u c e s u r f a c e t a c k i n e s s . T h e r e i s c o n s i d e r a b l e room f o r i m p r o v i n g e t h a n o l s w e l l i n g by r e d u c i n g c r o s s l i n k - d e n s i t y o r v a r y i n g comonomers. In T a b l e I h i g h water c o n t e n t (^ 20%) h y d r o g e l s a r e grouped i n the f i r s t s e t , P o l . 1 t o 5; a l l have h i g h g l a s s - t r a n s i t i o n tempera t u r e s ( T g ) . The low water c o n t e n t polymers a r e d i v i d e d i n t o mediumlow (7-10%, P o l . 6-8), low (^ 4%, P o l . 9) and v e r y - l o w ( 4 2-3%, P o l . 10-13) water c o n t e n t beads. The medium-low and v e r y - l o w groups a r e o r d e r e d by i n c r e a s i n g Tg, w h i c h p a r a l l e l s polymer p o l a r i t y , water c o n t e n t and, o f c o u r s e , EHA-content. Drug R e l e a s e from M o n o l i t h s R e l e a s e Rates and Volume E x p a n s i o n . The r e l e a s e o f d i c l o f e n a c - N a and o x p r e n o l o l - H C l f o l l o w s a f i r s t o r d e r p a t t e r n t y p i c a l f o r h y d r o g e l m o n o l i t h i c s p h e r e s w i t h a f a s t r e l e a s e phase up t o 70-80% c u m u l a t i v e r e l e a s e , f o l l o w e d by a phase of slow r e l e a s e , o f t e n c a l l e d ' t a i l i n g ( F i g u r e s 1 and 2 ) . The t time - a t w h i c h h a l f o f the l o a d e d drug i s r e l e a s e d - i s i n t h e s e c a s e s a good measure f o r the speed o f the i n i t i a l , o s m o t i c a l l y d r i v e n r e l e a s e phase; i t i s i n v e r s e l y p r o p o r t i o n a l t o t h e polymer's e q u i l i b r i u m water c o n t e n t ( F i g u r e 3 ) , even i f one t a k e s t h e d i f f e r e n c e s i n drug l o a d i n g s i n t o account ( T a b l e 1 ) . P h a s e - s e p a r a t e d P o l . 2 and 4 a l s o show s l o w e r r e l e a s e than p r e d i c t e d by t h e i r water c o n t e n t . Below ^ 4% water c o n t e n t the r e l e a s e becomes i n c r e a s i n g l y i n f l u e n c e d by the polymers g l a s s t r a n s i t i o n temperature; a f t e r an i n i t i a l b u r s t n e i t h e r DC1 nor OX i s r e l e a s e d from P o l . 10 beads, whose Tg i s below t h e r e l e a s e t e m p e r a t u r e , w h i l e P o l . 11 and 12, w h i c h a l s o have v e r y low water c o n t e n t but h i g h e r Tg, show a normal, o s m o t i c a l l y d r i v e n r e l e a s e phase ( F i g u r e 4). S i m i l a r t o the o b s e r v a t i o n s by Lee (11,12), the beads undergo g r e a t volume e x p a n s i o n d u r i n g the i n i t i a l r e l e a s e phase even w i t h p o o r l y s o l u b l e DC1 as a r e s u l t o f the o s m o t i c d r i v i n g f o r c e . The 1

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Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Lee and Good; Controlled-Release Technology ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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