`
`Exhibit 1015
`
`European Patent Application No. 0 040 590
`A2 (“EP ‘590”)
`
`

`

`Patentamt
`European Patent Office
`J E u r o p a i s c h e s
`Office europeen des brevets
`
`© Publication number:
`
`0 0 4 0 5 9 0
`A 2
`
`©
`
`EUROPEAN PATENT APPLICATION
`
`© Application number: 81850087.8
`^
`(22) Date of filing: 19.05.81
`
`© Int. CI.3: A 61 K 9/22
`A 61 K 9/32
`
`© Priority: 21.05.80 SE 8003805
`
`@ Date of publication of application:
`25.11.81 Bulletin 81/47
`© Designated Contracting States:
`AT BE CH DE FR GB IT LI LU NL SE
`
`©Applicant: Aktiebolaget Hassle
`S-431 83 Molndal(SE)
`© Inventor: Bogentoft, Conny Borje
`Backvagen 12
`S-430 50 Kallered(SE)
`© Representative: Wurm, Bengt Runio et al.
`Patent and Trade Mark Department Ab Astra
`S-151 85S6dertalje(SE)
`
`(54) A pharmaceutical preparation having improved release properties.
`An oral pharmaceutical preparation comprises a core
`containing a therapeutically active substance and a coating
`and is characterized in that the coating comprises an anionic
`carboxylic acrylic polymer soluble only above pH 5.5 in an
`amount of 10 to 85 per cent by weight of the coating and a
`waterinsoluble polymer selected from quaternary
`ammonium substituted acrylic polymers. The preparation
`enables release of a major part of the drug contents thereof in
`the lower part of the intestinal system.
`
`

`

`T e c h n i c a l f i e l d
`
`i n v e n t i o n
`The p r e s e n t
`to a p h a r m a c e u t i c a l p r e p a -
`is r e l a t e d
`r a t i o n f o r o r a l a d m i n i s t r a t i o n , h a v i n g
`i m p r o v e d r e l e a s e
`to a m e t h o d f o r p r e p a r i n g such p r e p a r a t i o n a n d
`p r o p e r t i e s ,
`to a m e t h o d of o b t a i n i n g an
`i m p r o v e d p r o f i l e of r e l e a s e o f
`the body of an a n i m a l or m a n .
`in
`a drug
`
`The o b j e c t of
`to o b t a i n a p r e p a r a t i o n w h i c h
`the
`i n v e n t i o n
`is
`the
`i t s drug c o n t e n t s
`in
`r e l e a s e s a m a j o r p a r t of
`l o w e r p a r t
`the
`in
`the
`of
`i n t e -
`i n t e s t i n a l s y s t e m p r e f e r e n t i a l l y
`l a r g e
`s t i n e
`i . e . c o l o n .
`
`B a c k g r o u n d a r t
`
`t h e r e l e a s e p r o p e r t i e s
`The p r e s e n t k n o w l e d g e of c o n t r o l of
`in an o r a l p h a r m a c e u t i c a l p r e p a r a t i o n
`is g r e a t and r a p i d l y
`in o r d e r to o b t a i n
`t h e use of c o a t i n g s
`g r o w i n g . E s p e c i a l l y
`a d e s i r e d r e l e a s e r a t e or r e l e a s e at a d e s i r e d
`l o c a t i o n
`i n
`in a n u m b e r
`the g a s t r o - i n t e s t i n a l s y s t e m has been d e s c r i b e d
`of p u b l i c a t i o n s among which US P a t e n t s 2 858 252, 2 853 4 2 0
`i l l u s t r a t i v e e x a m p l e s .
`and 3 835 221 c o u l d be m e n t i o n e d as
`i n c l u d i n g an e n t e r i c c o a t i n g on
`A number of p r e p a r a t i o n s
`t h u s k n o w n .
`t a b l e t s or s m a l l g r a n u l a r b o d i e s are
`
`is s t r o n g l y d e s i r a b l e
`it
`t o
`In c e r t a i n d i s e a s e c o n d i t i o n s
`the
`in
`i n t e s t i n e or
`t h e
`in
`o b t a i n drug r e l e a s e m a i n l y
`l a r g e
`i n t e s t i n e . T h i s
`the case e . g .
`the s m a l l
`is
`l o w e r f o u r t h of
`w i t h d r u g s used
`in
`the
`t r e a t m e n t of
`i n f l a m m a t o r y c o n d i t i o n s
`
`

`

`t h e c o l o n or
`i l e u m e.g._ C o l i t i s u l c e r o s a o r
`l o w e r
`in
`Morbus C r o h n . A n o t h e r t h e r a p e u t i c a r e a where such r e l e a s e
`the r e m o v a l of e x c e s s i v e a m o u n t s
`is
`p r o p e r t i e s are d e s i r e d
`in
`of b i l e a c i d
`t h e c o l o n u s i n g e . g . an a n i o n e x c h a n g e r
`such as c h o l e s t y r a m i n e . H o w e v e r , no p r e p a r a t i o n p r o v i d i n g
`is a v a i l a b l e .
`the d e s i r a b l e r e l e a s e p r o p e r t i e s
`
`In U. S. P a t e n t No. 3 , 9 5 7 , 5 2 3 a p r e p a r a t i o n w i t h a c o a t i n g
`is d e s c r i b e d , which has
`t h e o b j e c t of p r o v i d i n g
`c o m p o s i t i o n
`a c o n t r o l l e d
`i n t e s t i n a l r e l e a s e of a d r u g . S a i d c o a t i n g
`c o m p o s i t i o n c o m p r i s e s a m i x t u r e of an e n t e r o s o l u b l e c e l l u l o s e
`d e r i v a t i v e h a v i n g m o n o e s t e r
`l i n k a g e s w i t h a p o l y b a s i c a c i d
`and a d i g e s t i v e f l u i d - i n s o l u b l e c e l l u l o s e d e r i v a t i v e .
`the
`t h e c a s e
`t h a t one or both
`In
`two c o m p o n e n t s are s e l e c t e d
`t h e
`from v i n y l p o l y m e r s and a c r y l i c p o l y m e r s
`i n t e n d e d
`i n v e n t i o n
`i s . s t a t e d n o t
`o b j e c t of
`the
`t h u s known
`to b e
`o b t a i n a b l e .
`
`U. S. P a t e n t No. 3 , 4 3 1 , 3 3 8 d e s c r i b e s a p h a r m a c e u t i c a l
`(1) a m e d i c a m e n t - c o n t a i n i n g n u c l e u s ,
`c o m p o s i t i o n c o m p r i s i n g
`c o a t e d s e q u e n t i a l l y w i t h
`(2) a
`l a y e r of an a c i d - s o l u b l e
`is r e s i s t a n t b o t h
`to a l k a l i s a n d
`c o a t i n g m a t e r i a l w h i c h
`(3) a w a t e r - s o l u b l e
`i n t e s t i n a l
`i n t e r m e d i a t e
`j u i c e s ,
`l a y e r ,
`l a y e r of an a l k a l i s o l u b l e c o a t i n g m a t e r i a l w h i c h
`and
`(4) a
`to a c i d and g a s t r i c
`j u i c e s . Such c o m p o s i t i o n
`is r e s i s t a n t
`to e n a b l e r e l e a s e of a drug such as e m e t i n e o r
`is s a i d
`l o w e r s e c t i o n s of
`in
`the
`the s m a l l
`i n t e s t i n e
`d e h y d r o e m e t i n e
`the c o l o n , as c o n c l u d e d from r e l e a s e
`t e s t s on c o a t e d
`and
`i s
`such s e q u e n t i a l b u i l d - u p of a c o a t i n g
`t a b l e t s . H o w e v e r ,
`to g i v e a p r o d u c t
`i n c o n v e n i e n t and apt
`t e c h n i c a l l y h i g h l y
`w i t h u n r e l i a b l e p r o p e r t i e s .
`
`

`

`D i s c l o s u r e o f I n v e n t i o n
`
`t h a t
`it has been f o u n d
`i n v e n t i o n
`the p r e s e n t
`to
`A c c o r d i n g
`t h e r a p e u t i c a l l y a c t i v e
`by p r o v i d i n g a c o r e c o n t a i n i n g a
`s u b s t a n c e w i t h a c o a t i n g of a s p e c i f i e d c o m p o s i t i o n
`t h e
`the a c t i v e s u b s t a n c e can be d i r e c t e d
`r e l e a s e of
`to
`t h e
`the
`i l e u m o r b o t h as d e s i r e d ,
`the
`c o l o n or
`l o w e r p a r t of
`w h i l e d i s a d v a n t a g e s of p r e v i o u s l y known p r e p a r a t i o n s _ a r e
`a v o i d e d .
`
`i n v e n t i o n p r o v i d e s an o r a l p h a r m a c e u t i c a l
`the p r e s e n t
`Thus,
`p r e p a r a t i o n c o m p r i s i n g a c o r e c o n t a i n i n g a
`t h e r a p e u t i c a l l y
`a c t i v e s u b s t a n c e and a c o a t i n g , c h a r a c t e r i z e d
`in
`t h a t
`t h e
`c o a t i n g c o m p r i s e s an a n i o n i c c a r b o x y l i c a c r y l i c p o l y m e r
`s o l u b l e o n l y above pH 5.5
`in an amount of 10
`to 85 p e r
`c e n t by w e i g h t of
`the c o a t i n g and a w a t e r i n s o l u b l e p o l y m e r
`s e l e c t e d f r o m q u a r t e r n a r y ammonium s u b s t i t u t e d a c r y l i c
`to 90 p e r c e n t by w e i g h t o f
`in an amount of 15
`p o l y m e r s
`t h e c o a t i n g . The c o a t i n g n o r m a l l y has a
`t h i c k n e s s of 3-60 µm,
`p r e f e r a b l y 1 0 - 3 0 pm.
`
`in a d m i x t u r e
`The c o r e may c o n t a i n
`the a c t i v e s u b s t a n c e
`t h e s u r f a c e of a c a r r i e r
`w i t h c a r r i e r m a t e r i a l or on
`t h e c o r e may be made up of a c t i v e s u b s t a n c e
`p a r t i c l e , or
`o n l y .
`
`is meant a p o l y m e r c o n t a i n i n g a n i o n i c
`By an a n i o n i c p o l y m e r
`t h i s
`i n v e n t i o n such p o l y m e r
`the p u r p o s e of
`g r o u p s . For
`s h o u l d be s o l u b l e above pH 5 . 5 . P r e f e r a b l y
`the a n - i o n i c
`is s e l e c t e d
`from p a r t l y m e t h y l
`c a r b o x y l i c a c r y l i c p o l y m e r
`e s t e r i f i e d m e t h a c r y l i c a c i d p o l y m e r s .
`
`S u i t a b l e w a t e r i n s o l u b l e q u a r t e r n a r y ammonium s u b s t i t u t e d
`the n a m e s
`a c r y l i c p o l y m e r s are p o l y m e r s s o l d u n d e r
`E u d r a g i t RS and E u d r a g i t RL, h a v i n g an ammonium s u b s t i t u t i o n
`of a b o u t 5 and a b o u t 10 p e r c e n t by w e i g h t ,
`r e s p e c t i v e l y .
`
`

`

`S u i t a b l e p a r t l y m e t h y l e s t e r i f i e d m e t h a c r y l i c a c i d
`p o l y m e r s are s o l d u n d e r the names E u d r a g i t L a n d E u d r a g i t S .
`
`A c c o r d i n g
`
`to a p r e f e r r e d e m b o d i m e n t of
`
`t h e
`
`i n v e n t i o n
`
`t h e
`
`c o a t i n g c o m p o s i t i o n a d d i t i o n a l l y c o m p r i s e s a p l a s t i c i z e r
`s e l e c t e d from f a t t y a l c o h o l s or f a t t y a c i d s . E s p e c i a l l y
`( c e t y l a l c o h o l ) a n d
`s u i t a b l e p l a s t i c i z e r s are c e t a n o l
`s t e a r i c a c i d . The amount of p l a s t i c i z e r
`is s u i t a b l y up
`the c o a t i n g .
`25 per c e n t by w e i g h t of
`
`t o
`
`to be
`t h e r a p e u t i c a l l y a c t i v e s u b s t a n c e s
`i n c l u d e d
`P r e f e r r e d
`i n v e n t i o n a r e
`t h e
`in a p h a r m a c e u t i c a l p r e p a r a t i o n of
`s a l i c y l a z o - s u l f a p y r i d i n e , 5 - a m i n o s a l i c y l i c a c i d a n d
`c h o l e s t y r a m i n e , as w e l l as s a l t s and r e l a t e d c o m p o u n d s
`h a v i n g s i m i l a r t h e r a p e u t i c p r o p e r t i e s .
`
`t h e
`i n v e n t i o n are
`The c o a t e d c o r e s of
`i n c l u d e d
`to be
`i n
`d o s a g e u n i t s . N o r m a l l y each d o s a g e u n i t c o n t a i n s at
`l e a s t
`the minimum n u m b e r of b o d i e s
`a b o u t 10 b o d i e s . P r e f e r a b l y
`i s
`a b o u t 200. Among s u i t a b l e d o s a g e u n i t s
`t a b l e t s and c a p s u l e s -
`are s p e c i f i c a l l y m e n t i o n e d . P h a r m a c e u t i c a l l y a c c e p t a b l e
`i n c l u d e d
`in
`the d o s a g e u n i t s
`a d d i t i v e s may be
`t o g e t h e r w i t h
`the
`the p r e p a r a t i o n of
`i n v e n t i o n .
`
`the p r e p a r a t i o n may
`t h e b o d i e s of
`The c o r e s of
`i n c l u d e
`t h e
`i n d i f f e r e n t m a t e r i a l s of
`p h a r m a c e u t i c a l l y
`t y p e n o r m a l l y
`in p h a r m a c e u t i c a l p r e p a r a t i o n s ,
`u s e d
`s u c h as p o l y s a c c h a r i d e s ,
`m i c r o c r y s t a l l i n e c e l l u l o s e , s t a r c h and w a x e s . The s i z e o f
`t h e c o r e s may be s i e v e f r a c t i o n s b e t w e e n 0.1 and 3.0 mm,
`p r e f e r a b l y b e t w e e n 0.5 and 1.5 mm.
`
`

`

`is a p r o c e s s f o r
`i n v e n t i o n
`the p r e s e n t
`A n o t h e r a s p e c t of
`p r e p a r i n g a p h a r m a c e u t i c a l p r e p a r a t i o n as d e f i n e d a b o v e ,
`l a r g e n u m b e r o f
`t h a t a
`in
`is c h a r a c t e r i z e d
`which p r o c e s s
`c o r e s as d e f i n e d above are p r o v i d e d w i t h a c o a t i n g a s
`t h e c o a t i n g
`d e f i n e d a b o v e by a p p l y i n g a s o l u t i o n of
`is p r e f e r a b l y a p p l i e d
`the c o r e s . The c o a t i n g
`to
`c o m p o s i t i o n
`the c o a t i n g s o l u t i o n .
`by s p r a y i n g
`
`the p r o c e s s of
`t h e
`to
`The s o l v e n t s e m p l o y e d a c c o r d i n g
`i n v e n t i o n are s o l v e n t s h a v i n g a s u f f i c i e n t v o l a t i l i t y
`t o
`e v a p o r a t e u n d e r the c o n d i t i o n s of a p p l i c a t i o n ,
`l e a v i n g a
`t h e s o l u t e on
`the s u r f a c e of
`l a y e r of
`t h e c o r e or b o d y
`p r e p a r e d . P r e f e r a b l y o r g a n i c s o l v e n t s such as a l c o h o l s ,
`h y d r o c a r b o n s and e s t e r s are used as w e l l as d e r i v a t i v e s
`such as c h l o r i n a t e d h y d r o c a r b o n s . The p r o c e s s o f
`t h e r e o f ,
`t h e c o a t i n g may be c a r r i e d out
`in an a p p a r a t u s
`a p p l y i n g
`in
`n o r m a l l y used
`the p h a r m a c e u t i c a l
`i n d u s t r y f o r c o a t i n g
`of s o l i d p h a r m a c e u t i c a l p r e p a r a t i o n s , p r e f e r a b l y
`in a f l u i d
`is n o r m a l l y c a r r i e d out a t
`bed a p p a r a t u s . The p r o c e s s
`a m b i e n t c o n d i t i o n s , h o w e v e r ,
`t e m p e r a t u r e and p r e s s u r e
`c o n d i t i o n s may be v a r i e d w i t h i n b r o a d ' l i m i t s .
`In a f l u i d
`t h e
`t e m p e r a t u r e of
`the
`i n l e t a i r
`i s
`bed s p r a y i n g p r o c e s s
`to 6 0 ° C .
`s u i t a b l y 1 5
`
`i n v e n t i o n are a c o a t i n g c o m p o s i t i o n
`F u r h t e r a s p e c t s of
`t h e
`as d e f i n e d above and a method of o b t a i n i n g r e l e a s e of a
`in
`t h e
`t h e
`t h e r a p e u t i c a l l y a c t i v e s u b s t a n c e
`l o w e r p a r t of
`i n t e s t i n a l s y s t e m and a method of
`t r e a t m e n t , b o t h e m p l o y i n g
`the p r e p a r a t i o n d e f i n e d a b o v e .
`
`The
`
`the
`t h a t
`the
`t a k e s a d v a n t a g e of
`i n v e n t i o n
`t i m e o f
`f a c t
`the s m a l l
`i n t e s t i n e
`r a t h e r c o n s t a n t
`is
`t h r o u g h
`p a s s a g e
`in d i s e a s e c o n d i t i o n s c o n n e c t e d w i t h d i a r r h o e a o r
`even
`to 5 h o u r s .
`in man s a i d
`t i m e
`is 2
`o b s t i p a t i o n . Thus,
`the
`the c h a n g e of pH from a c i d
`to
`i n v e n t i o n
`A c c o r d i n g
`a b o u t n e u t r a l at
`the p y l o r u s
`is e m p l o y e d as a
`t r i g g e r
`the p h y s i c a l c o n d i t i o n of
`m e c h a n i s m c h a n g i n g
`the c o a t i n g
`
`t o
`
`

`

`and f i n a l l y c a u s i n g r e l e a s e of
`t i m e .
`a p r e d e t e r m i n e d
`lag
`
`t h e a c t i v e s u b s t a n c e a f t e r
`
`E x p e r i m e n t a l .
`
`T e s t s on
`
`r e l e a s e p r o p e r t i e s
`
`t h e r e l e a s e p r o p e r t i e s
`As a model s u b s t a n c e f o r s t u d y of
`(SASP) was u s e d . SASP
`is a b s o r b e d
`s a l i c y l a z o - s u l f a p y r i d i n e
`t h e s t o m a c h and
`the s m a l l
`in
`to a s m a l l e x t e n t
`i n t e s t i n e .
`i t
`is c o m p l e t e l y b r o k e n down by b a c t e r i a
`In
`the c o l o n
`t o
`(SP) and 5 - a m i n o - s a l i c y l i c a c i d
`( 5 - A S A )
`s u l f a p y r i d i n e
`t h e n a b s o r b e d .
`which are
`
`With a c o n v e n t i o n a l p r e p a r a t i o n of SASP a b o u t 5 % of
`t h e
`in
`the u r i n e due
`is e x c r e t e d as SASP
`to a b s o r b t i o n
`d o s a g e
`i n t e s t i n e . The t o t a l e x c r e t e d a m o u n t s of SP
`in
`t h e s m a l l
`and 5-ASA are a b o u t 75 % and 25 % r e s p e c t i v e l y . With a
`t h e e x c r e t e d amount of SASP w o u l d
`c o l o n r e l e a s e p r e p a r a t i o n
`be s t r o n g l y r e d u c e d w h i l e
`t h e e x c r e t e d a m o u n t s of SP a n d
`5-ASA would be s u b s t a n t i a l l y u n c h a n g e d or i n c r e a s e d .
`
`P r e p a r a t i o n
`
`The
`
`t e s t p r e p a r a t i o n were p r e p a r e d as f o l l o w s :
`
`(120 g), w e r e
`c e t a n o l
`(1960 g),
`(2000 g),
`SASP
`l a c t o s e
`(1000 g )
`mixed f o r 10 m i n u t e s
`in a p l a n e t m i x e r . W a t e r
`c o n t a i n i n g 25 g c a r b o x y m e t h y l c e l l u l o s e was
`t h e n _ a d d e d
`s l o w l y f o r 2 m i n u t e s w h e r e u p o n
`the m i x i n g c o n t i n u e d f o r
`10 m i n u t e s . The wet m i x t u r e was
`t h e n e x t r u d e d and s p h e r o n i z e d .
`t h e n d r i e d at 500C f o r 1 h o u r in a f l u i d
`The g r a n u l e s were
`bed. The c o r e s had
`t h e f o l l o w i n g s i e v e a n a l y s i s :
`
`

`

`T e s t s
`
`in v i t r o
`
`the b e a k e r
`The r a t e of r e l e a s e of SASP was d e t e r m i n e d by
`(Levy et a l . , New E n g l a n d J o u r n a l of M e d i c i n e ,
`method
`( 1 9 6 0 ) ) at 37°C and 100 rpm
`v o l . 262, p. 1 0 5 3 - 1 0 5 8
`i n
`p h o s p h a t e b u f f e r s h a v i n g pH 6.7 and 7 . 0 .
`S a m p l e s w e r e
`t h e a m o u n t of S A S P ' r e l e a s e d
`t a k e n at d i f f e r e n t
`t i m e s and
`was d e t e r m i n e d s p e c t r o p h o t o m e t r i c a l l y . The c o r e s w e r e
`c o a t e d by a i r b o r n e s p r a y i n g . 500 g p o r t i o n s of g r a n u l e s
`the f o l l o w i n g c o a t i n g s o l u t i o n s
`were c o a t e d w i t h each of
`i n v e n t i o n :
`to
`the p r e s e n t
`a c c o r d i n g
`
`t h e
`
`t e s t s were made by
`R e l e a s e
`the same m e t h o d as w i t h
`core m a t e r i a l . A c o n v e n t i o n a l
`t a b l e t p r e p a r a t i o n
`( S a l a z o p y r i n ® ) was a l s o s t u d i e d . The
`r e s u l t s of
`t e s t s are g i v e n b e l o w .
`
`t h e
`
`r e l e a s e
`
`

`

`Per c e n t SASP r e l e a s e d at pH 6 . 7
`
`Per c e n t r e l e a s e d at pH 7 . 0
`
`T e s t s
`
`in v i v o
`
`t e s t p e r s o n s w i t h an a v e r a g e a g e
`Seven h e a l t h y v o l u n t a r y
`t h e
`( 2 6 - 5 4 ) p a r t i c i p a t e d . The
`t a b l e t and
`t w o
`of 34 y e a r s
`the
`i n v e n t i o n d e s c r i b e d above were
`p r e p a r a t i o n s of
`t e s t e d .
`the
`The g r a n u l a r p r e p a r a t i o n s of
`i n v e n t i o n were a d m i n i s t e r e d
`in a h a r d g e l a t i n e c a p s u l e . All p r e p a r a t i o n s were g i v e n
`i n
`r a n d o m i z e d w i t h a c r o s s - o v e r t e c h n i q u e . T o t a l l y
`one d o s e ,
`a d o s a g e of 2 g SASP of each p r e p a r a t i o n was g i v e n ,
`i . e .
`t a b l e t s or 7 c a p s u l e s of each g r a n u l a r p r e p a r a t i o n .
`4
`
`t e s t p r e p a r a t i o n w a s
`l e a s t 10 h o u r s f a s t i n g
`A f t e r at
`t h e
`l a t e r r e s t r i c t i o n s
`i n g e s t e d w i t h 200 ml w a t e r . T h r e e h o u r s
`l i f t e d . All u r i n e was c o l l e c t e d f o r 4 d a y s .
`on f e e d i n g were
`At
`l e a s t 7 days p a s s e d b e t w e e n each
`t e s t p e r i o d . The u r i n e
`s a m p l e s were s t o r e d d e e p - f r o z e n b e f o r e a n a l y s i s . All u r i n e
`
`

`

`s a m p l e s were a n a l y z e d f o r SASP and a c e t y l - 5 - A S A by
`l i q u i d
`c h r o m a t o g r a p h y m e t h o d s . The
`l a t t e r s u b s t a n c e , which
`is a
`m e t a b o l i t e of 5-ASA, was c h o s e n f o r a n a l y s i s as
`l a r g e l y
`t o t a l e x c r e t i o n of 5 - A S A .
`t h e
`r e p r e s e n t i n g
`
`S t a t i s t i c s i g n i f i c a n c e
`( p < 0 . 0 5 ) was c o m p u t e d by p a i r e d
`t e s t .
`t - t e s t and W i l c o x o n
`
`in u r i n e of SASP and a c e t y l - 5 - A S A
`Amounts e x c r e t e d
`t a b l e b e l o w w i t h m e a n v a l u e s and SEM
`in
`the
`shown
`the m e a n s ) .
`e r r o r of
`
`i s
`( s t a n d a r d
`
`in u r i n e d u r i n g
`Amounts of SASP and a c e t y l - 5 - A S A e x c r e t e d
`4 days a f t e r a d m i n i s t r a t i o n of 2 g of SASP:
`
`C o m m e n t s
`
`i n v e n t i o n a c c o r d i n g
`t h e
`The p r e p a r a t i o n s of
`to E x a m p l e 1
`and Example 2 gave a s i g n i f i c a n t l y
`l o w e r e d a m o u n t o f
`to
`the
`t a b l e t . Between s a i d
`e x c r e t e d SASP as c o m p a r e d
`t w o
`i n v e n t i o n no s i g n i f i c a n t d i f f e r e n c e
`the
`p r e p a r a t i o n s of
`was f o u n d . The e x c r e t e d a m o u n t s of SASP
`in u r i n e d e c r e a s e
`in v i t r o . The a m o u n t s
`with d e c r e a s i n g r e l e a s e r a t e
`e x c r e t e d of a c e t y l - 5 - A S A was not s i g n i f i c a n t l y d i f f e r e n t
`t e s t e d .
`the t h r e e p r e p a r a t i o n s
`b e t w e e n
`
`

`

`10
`
`0040590
`
`The r e s u l t s c o n f i r m t h a t a p r e p a r a t i o n g i v i n g
`t h e d e s i r e d
`The results confirm that a preparation giving the desired
`is o b t a i n a b l e by
`the p r e s e n t
`r e l e a s e p r o p e r t i e s
`i n v e n t i o n .
`release properties is obtainable by the present invention.
`
`i l l u s t r a t e d by e x a m p l e s a n d
`is f u r t h e r
`i n v e n t i o n
`The
`The invention is further illustrated by examples and
`the b e a k e r m e t h o d g i v e n
`t e s t s a c c o r d i n g
`to
`in
`t h e
`r e l e a s e
`release tests according to the beaker method given in the
`t a b l e b e l o w .
`table below.
`
`
`

`

`
`
`A,.A..T...,_.,.,2Y...,.:
`
`
`
`wucwumnsmm>muumW0u.G5OE¢
`
`
`
`umwummmmamm
`
`Hmumuwummam
`
`uaazxopumuumco«c<
`wansaomamuwumz
`
`
`
`uwfizaomuflamuom
`
`uwemaom
`
`mmasamummomoomouAwvmuamcomaoo
`
`wafiumoo
`
`
`
`1...4.4,3.
`
`T.n.1.PD.DWmmmN.uMmmuamumnzmmamemxm
`
`m>wuu<
`
`11
`
`0040590
`
`mm
`
`
`
`.x.
`
`Ionmamuwamm
`
`om0ANado»o
`AHmcmvmpzamImmadm
`
`m.hHAmwfluwNumazomamm
`
`Ioc«E<|m
`
`omamuflamw
`
`IHmumu<
`
`mm
`
`om
`
`_
`
`2‘N
`
`:m
`
`;oaNHsM1MmMwMmuoucaoz
`
`
`uuwummvmmmmamuam.am.0am.0am.
`
`
`
`
`
`

`

`F o o t n o t e s
`
`1) C o r e s had a c o m p o s i t i o n and were p r e p a r e d as d e s c r i b e d
`u n d e r " T e s t s on r e l e a s e p r o p e r t i e s " a b o v e .
`
`2)
`
`3)
`
`C o m p r e s s e d 100 % a c e t y l s a l i c y l i c a c i d g r a n u l e s
`( A S A - G r a n , M o n s a n t o ) .
`
`in E x a m p l e 7 c o n s i s t e d of 75 % a c t i v e s u b s t a n c e ,
`C o r e s
`( P l u r o n i c ® ) .
`25 % c e l l u l o s e a v i c e l and 5 % p o l o x a l e n e
`t h e p r o c e s s r e f e r r e d
`The c o r e s were p r e p a r e d by
`t o
`u n d e r
`l ) .
`
`B e s t m o d e o f c a r r i n o u t t h e i n v e n t i o n
`
`t h e
`The b e s t mode of c a r r y i n g out
`to E x a m p l e
`e m b o d i m e n t a c c o r d i n g
`7
`
`i n v e n t i o n
`a b o v e .
`
`is
`
`t h e
`
`

`

`1. An o r a l p h a r m a c e u t i c a l p r e p a r a t i o n c o m p r i s i n g a c o r e
`t h e r a p e u t i c a l l y a c t i v e s u b s t a n c e and a
`c o n t a i n i n g a
`the c o a t i n g c o m p r i s e s a n
`c o a t i n g , c h a r a c t e r i z e d
`t h a t
`in
`a n i o n i c c a r b o x y l i c a c r y l i c p o l y m e r s o l u b l e o n l y a b o v e
`to 8 5 p e r c e n t by w e i g h t of
`in an a m o u n t of 1D
`pH 5.5
`c o a t i n g and a w a t e r i n s o l u b l e p o l y m e r s e l e c t e d f r o m
`in a n
`q u a r t e r n a r y ammonium s u b s t i t u t e d a c r y l i c p o l y m e r s
`t h e c o a t i n g .
`to 90 p e r c e n t by w e i g h t of
`amount of 15
`
`t h e
`
`i n
`to c l a i m 1 , . c h a r a c t e r i z e d
`2. A p r e p a r a t i o n a c c o r d i n g
`is s e l e c t e d
`t h e a n i o n i c c a r b o x y l i c a c r y l i c p o l y m e r
`t h a t
`from p a r t l y m e t h y l e s t e r i f i e d m e t h a c r y l i c a c i d p o l y m e r s .
`
`t h e p r e c e d i n g
`to one or more of
`3. A p r e p a r a t i o n a c c o r d i n g
`c l a i m s , c h a r a c t e r i z e d
`in
`t h a t
`the c o a t i n g c o m p o s i t i o n
`a d d i t i o n a l l y c o m p r i s e s a p l a s t i c i z e r s e l e c t e d from f a t t y
`a l c o h o l s or f a t t y a c i d s .
`
`4. A p r o c e s s f o r p r e p a r i n g an o r a l p h a r m a c e u t i c a l p r e p a r a -
`t h e r a p e u t i c a l l y a c t i v e
`t i o n c o m p r i s i n g .a c o r e c o n t a i n i n g a
`in
`t h a t a
`s u b s t a n c e and a c o a t i n g , c h a r a c t e r i z e d
`l a r g e
`number of c o r e s are c o a t e d w i t h a c o m p o s i t i o n c o m p r i s i n g
`an a n i o n i c c a r b o x y l i c a c r y l i c p o l y m e r s o l u b l e o n l y a b o v e
`to 85 p e r c e n t by w e i g h t and a
`in an amount of 10
`pH 5.5
`w a t e r i n s o l u b l e p o l y m e r s e l e c t e d from q u a r t e r n a r y a m m o n i u m
`to 90 p e r
`in an amount of 15
`s u b s t i t u t e d a c r y l i c p o l y m e r s
`the c o a t i n g , by a p p l y i n g a s o l u t i o n of
`t h e
`c e n t of
`to
`the c o r e s .
`c o m p o s i t i o n
`
`in
`the d r y
`t h a t
`5. A c o a t i n g c o m p o s i t i o n c h a r a c t e r i z e d
`t h e r e o f c o m p r i s e s an a n i o n i c c a r b o x y l i c a c r y l i c
`s u b s t a n c e
`to 85
`in an amount of 10
`p o l y m e r s o l u b l e o n l y above pH 5.5
`per c e n t by w e i g h t and a w a t e r i n s o l u b l e p o l y m e r s e l e c t e d
`i n
`from q u a r t e r n a r y ammonium s u b s t i t u t e d a c r y l i c p o l y m e r s
`to 90 p e r c e n t by w e i g h t of
`t h e c o a t i n g .
`an amount of 15
`
`

`

`6. A m e t h o d of o b t a i n i n g r e l e a s e of a
`t h e r a p e u t i c a l l y
`in
`t h e
`a c t i v e s u b s t a n c e
`the
`i n t e s t i n a l
`l o w e r p a r t of
`in a d m i n i s t e r i n g
`s y s t e m of an a n i m a l or man, c h a r a c t e r i z e d
`to such h o s t a p r e p a r a t i o n a c c o r d i n g
`to c l a i m 1 .
`o r a l l y
`
`i n .
`t r e a t m e n t of
`7. A m e t h o d of
`i n f l a m m a t o r y c o n d i t i o n s
`l o w e r
`in an a n i m a l or man, c h a r a c t e r i z e d
`i l e u m
`the c o l o n or
`to a h o s t s u f f e r i n g from s u c h
`in a d m i n i s t e r i n g o r a l l y
`c o n d i t i o n s an e f f e c t i v e a m o u n t of a p r e p a r a t i o n a c c o r d i n g
`to c l a i m 1 .
`
`8. An o r a l p h a r m a c e u t i c a l p r e p a r a t i o n , a p r o c e s s , a
`c o a t i n g c o m p o s i t i o n , a m e t h o d of o b t a i n i n g r e l e a s e or a
`m e t h o d of
`t r e a t m e n t as c l a i m e d
`in one or more of c l a i m s
`1-7 and s u b s t a n t i a l l y as d e s c r i b e d .
`
`