Transbuccal Absorption of Diclofenac Sodium in a Dog Model - ACS

Chapter 23

Transbuccal Absorption of Diclofenac Sodium in a Dog Model C. D. Ebert, V. A. John, P. T. Beall, and K. A. Rosenzweig

Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch023

Basic Pharmaceutics Research, Ciba-Geigy Corporation, Ardsley, NY 10502

The buccal permeability of the non-steroidal antiinflammatory drug, diclofenac sodium, has been evaluated in a dog model. The dog was selected because of the similarity of its buccal mucosa to that of man. Analysis of the buccal data indicated that diclofenac sodium permeability followed an essentially zero-order kinetic process with a minimal lag phase. Permeability of the drug was estimated to be 3 mg/cm .h but significant differences were observed between animals. The absorption rate with the transbuccal delivery device decreased with time whereas the corresponding rate with a saturated solution was constant. This difference was attributed to the time dependency of drug delivery from the device and was modeled on the basis of release from a membranedispersed monolith combined with constant buccal permeability. The predictions of the model showed excellent agreement with the experimental data. 2

B u c c a l a d m i n i s t r a t i o n o f f e r s c e r t a i n unique advantages f o r drugs which cannot be e a s i l y o r e f f i c i e n t l y a d m i n i s t e r e d by t h e o r a l o r intravenous route. However, t r a n s b u c c a l drug d e l i v e r y has r e c e i v e d r e l a t i v e l y l i t t l e a t t e n t i o n and few w e l l - c o n t r o l l e d s t u d i e s o f b u c c a l mucosa p e r m e a b i l i t y have been c o n d u c t e d . The o r a l mucosa p r o v i d e s a p r o t e c t i v e c o v e r i n g f o r u n d e r l y i n g t i s s u e s w h i l e a c t i n g as a b a r r i e r t o t h e e n t r y o f m i c r o o r g a n i s m s and t o x i n s . H i s t o l o g i c a l l y , the s t r a t i f i e d squamous e p i t h e l i u m l i n i n g t h e o r a l c a v i t y e x h i b i t s a d i v e r s e s t r u c t u r e as w e l l as i m p o r t a n t i n t e r - s p e c i e s d i f f e r e n c e s . This

0097-6156/87/0348-0310S06.00/0 © 1987 American Chemical Society

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


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o b s e r v a t i o n has c o n s i d e r a b l e s i g n i f i c a n c e i n t h e t e s t i n g o f b u c c a l p e r m e a b i l i t y both i n terms o f c o n t r o l l i n g t h e s i t e and a r e a o f a d m i n i s t r a t i o n and e n s u r i n g c o m p a r a b i l i t y i n mucosal s t r u c t u r e between a s e l e c t e d a n i m a l model and man. I n t h e p r e s e n t i n v e s t i g a t i o n a number o f a n i m a l s p e c i e s were s c r e e n e d b e f o r e t h e dog was chosen as t h e most a p p r o p r i a t e model. Many f a c t o r s i n c l u d i n g p a r t i t i o n c h a r a c t e r i s t i c s , degree o f i o n i z a t i o n , m o l e c u l a r s i z e e t c . i n f l u e n c e t h e t r a n s p o r t o f drugs a c r o s s b i o l o g i c a l membranes. P e r m e a t i o n o f i n t a c t mucosa may a l s o i n v o l v e p a s s i v e d i f f u s i o n , i n t e r c e l l u l a r movement, t r a n s p o r t through pores o r o t h e r mechanisms. The o b j e c t i v e o f t h e s t u d i e s r e p o r t e d here was t o employ t h e dog model t o i n v e s t i g a t e t h e s e f a c t o r s i n a s y s t e m a t i c and e x p e r i m e n t a l l y w e l l - c o n t r o l l e d fashion. The n o n - s t e r i o d a l a n t i - i n f l a m m a t o r y drug, d i c l o f e n a c sodium, was s e l e c t e d as a t e s t compound i n t h i s e v a l u a t i o n process. C h a r a c t e r i z a t i o n of the buccal permeability of d i c l o f e n a c sodium from both a s a t u r a t e d s o l u t i o n and an e x p e r i m e n t a l drug d e l i v e r y device c o n s i s t e d of: 1 ) d e f i n i n g the d i s p o s i t i o n k i n e t i c s o f t h e drug a f t e r b o l u s i n t r a v e n o u s a d m i n i s t r a t i o n , 2 ) d e c o n v o l u t i n g t h e plasma c o n c e n t r a t i o n / t i m e p r o f i l e s a f t e r b u c c a l a d m i n i s t r a t i o n u s i n g t h e parameters e s t i m a t e d from t h e i n t r a v e n o u s d a t a , and 3 ) d e f i n i n g t h e t o t a l amount absorbed by r e s i d u a l drug a n a l y s i s o f t h e r e m a i n i n g s o l u t i o n o r d e p l e t e d system. I n a d d i t i o n a model was d e v e l o p e d which i n c o r p o r a t e d t h e release c h a r a c t e r i s t i c s of the d e l i v e r y device i n t o the o v e r a l l p r o c e s s o f b u c c a l drug a b s o r p t i o n . T h i s model a l l o w e d t h e r e l a t i v e c o n t r i b u t i o n s o f t h e d e v i c e and b i o l o g i c a l membrane t o be i n v e s t i g a t e d . Experimental B u c c a l Mucosa H i s t o l o g y . T i s s u e b i o p s i e s were t a k e n from t h e c e n t e r o f t h e i n n e r cheek o f the o r a l mucosa i n hamster, g u i n e a p i g , r a t , r a b b i t , dog and mini-pig. The t i s s u e s were f i x e d i n f o r m a l i n , d e h y d r a t e d i n e t h a n o l and x y l e n e and embedded i n p a r a f i n wax. The p a r a f i n b l o c k s were microtomed and t h e s e c t i o n s s t a i n e d w i t h E o s i n / H a e m o t o x a l i n f o r e x a m i n a t i o n by l i g h t m i c r o s c o p y . Analytical

Technique.

D i c l o f e n a c sodium c o n c e n t r a t i o n s i n aqueous s o l u t i o n s and i n plasma were e s t i m a t e d by means o f a p u b l i s h e d h i g h performance l i q u i d chromatographic technique ( J _ ) . T h i s method had a d e t e c t i o n l i m i t o f 5 ng/ml and gave r e p l i c a t e v a l u e s w i t h i n ± 1 0 % at l e v e l s above 2 0 ng/ml. C a l i b r a t i o n curves were l i n e a r throughout t h e range o f measured c o n c e n t r a t i o n s .


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Transbuccal D e l i v e r y Device. E x p e r i m e n t a l t r a n s b u c c a l drug d e l i v e r y d e v i c e s were p r e p a r e d from 0.4 mm t h i c k two-component h y d r o g e l f i l m s c o n s i s t i n g o f p-HEMA w i t h h y d r o p h o b i c d i f u n c t i o n a l macromolecular c r o s s l i n k s ( 2 ) . A monomer m i x t u r e c o n t a i n i n g 80% (ν/ν) HEMA w i t h 20% ( v / v ) macromolecular c r o s s l i n k e r was used f o r a l l d e v i c e p o l y m e r i z a t i o n s . R e s u l t a n t h y d r o g e l s produce 38% and 120% s w e l l i n g i n water and 70% ( v / v ) e t h a n o l , r e s p e c t i v e l y . Polymerized f i l m s ( 0 . ^ mm t h i c k were e x t r a c t e d i n water f o r 24 h b e f o r e d i s c s o f lcm s u r f a c e a r e a were p r e p a r e d . These d i s c s were e x h a u s t i v e l y e x t r a c t e d i n e t h a n o l a t 45°C, and vacuum d r i e d . Diclofenac sodium was l o a d e d by suspending the d i s c s i n a 42% (wt/v) drug s o l u t i o n i n 82% ( v / v ) methanol/water at room temperature f o r 24 h. The e q u i l i b r a t e d d i s c s were then removed and q u i c k l y immersed i n a drug f r e e methanol/water s o l u t i o n of the same c o m p o s i t i o n t o remove excess drug from the d i s c s u r f a c e . Loaded d i s c s were vacuum d r i e d and s t o r e d under d e s s i c a t i o n . The d i s c s were p r e h y d r a t e d a t 45°C i n 95% h u m i d i t y chambers f o r 24 h p r i o r t o use. In V i t r o

Release

In v i t r o drug r e l e a s e from t r a n s b u c c a l d i s c d e v i c e s was d e t e r mined a t 37°C u s i n g a USP d i s s o l u t i o n a p p a r a t u s connected through a m i c r o p r o c e s s o r - c o n t r o l l e d p e r i s t a l t i c pump t o a f r a c t i o n collector. The c u m u l a t i v e amount r e l e a s e d as a f u n c t i o n of time was c a l c u l a t e d from the drug c o n c e n t r a t i o n d a t a a f t e r compensating f o r the t o t a l amount removed i n the c o l l e c t e d sample fractions. In V i v o Animal Studies The d i s p o s i t i o n k i n e t i c s o f d i c l o f e n a c was determined i n awake Beagle dogs a f t e r s i n g l e i n t r a v e n o u s b o l u s a d m i n i s t r a t i o n o f a 4 mg dose. The i n t r a v e n o u s dose was a d m i n i s t e r e d i n t o the l e f t c e p h a l i c v e i n . B l o o d samples (3 ml) were drawn from the v e i n i n the o p p o s i t e l e g a t i n t e r v a l s over 30 h a f t e r d o s i n g . These samples were h e p a r i n i z e d and c e n t r i f u g e d immediately t o i s o l a t e the plasma f r a c t i o n . Samples were s t o r e d f r o z e n u n t i l a n a l y z e d . B u c c a l s t u d i e s were performed i n the same beagle dogs under l i g h t Nembutal a n a e s t h e s i a . The dog was p o s i t i o n e d on a s u r g i c a l t a b l e , the mouth was braced open and the tongue taped t o the upper jaw. V i t a l body f u n c t i o n s were c a r e f u l l y monitored d u r i n g the p e r i o d of a n a e s t h e s i a and a d d i t i o n a l doses o f Nembutal a d m i n i s t e r e d as r e q u i r e d . The p r o c e d u r e s employed complied w i t h a l l e x i s t i n g s t a n d a r d o p e r a t i n g p r o c e d u r e s , and the a r e a of drug



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exposure was r e g u l a r l y checked t o e n s u r e t h a t t h e mucosa was n o t b e i n g s i g n i f i c a n t l y damaged. A b s o r p t i o n from s a t u r a t e d aqueous s o l u t i o n s (39 mg/ml a t |7°C) was e v a l u a t e d by p l a c i n g a g l a s s d i f f u s i o n c e l l o f 1.5cm i n t e r n a l s u r f a c e a r e a on t h e i n n e r c e n t r a l buccal surface u s i n g e i t h e r s i l i c o n e grease or mechanical clamping f o r a s e a l . A 1 ml a l i q u o t o f t h e s a t u r a t e d s o l u t i o n was i n t r o d u c e d i n t o t h e c e l l and b l o o d samples c o l l e c t e d a s p r e v i o u s l y d e s c r i b e d . A t 4 h t h e drug s o l u t i o n was a s p i r a t e d from t h e c e l l f o r q u a n t i t a t i o n o f t h e t o t a l amount a b s o r b e d . The above p r o c e d u r e was a l s o employed t o i n v e s t i g a t e b u c c a l a b s o r p t i o n from t h e HEMAC e x p e r i m e n t a l d e l i v e r y d e v i c e . As i n t h e c a s e o f t h e d i f f u s i o n c e l l t h e d r u g - l o a d e d d i s c was p o s i t i o n e d on t h e i n n e r c e n t r a l s u r f a c e o f t h e b u c c a l mucosa. An impermeable f i l m c o a t e d w i t h mucosal a d h e s i v e (F-4000, A d h e s i v e s R e s e a r c h , G l e n Rock, PA) on t h e p e r i p h e r y was t h e n p o s i t i o n e d over t h e HEMAC d i s c t o p r e v e n t d e h y d r a t i o n and t o s e c u r e t h e d e v i c e i n p l a c e on t h e mucosal s u r f a c e . The d i s c was a l l o w e d t o remain i n c o n t a c t w i t h t h e mucosa f o r 4 h b e f o r e i t was removed f o r q u a n t i t a t i o n o f r e s i d u a l drug c o n t e n t . B l o o d samples were c o l l e c t e d over t h e same i n t e r v a l a s f o r t h e s a t u r a t e d s o l u t i o n and p r o c e s s e d i n t h e same manner. Data A n a l y s i s . Plasma concentrâtion/time p r o f i l e s a f t e r i n t r a v e n o u s d o s i n g were a n a l y z e d i n terms o f a two-compartment p h a r m a c o k i n e t i c model. The b i e x p o n e n t i a l r a t e e q u a t i o n a s s o c i a t e d w i t h t h i s model was f i t t e d t o t h e e x p e r i m e n t a l d a t a u s i n g a n o n l i n e a r l e a s t squares procedure. P h a r m a c o k i n e t i c c o n s t a n t s f o r t h e two-compartment model were c a l c u l a t e d by s t a n d a r d methods. The f r a c t i o n amount absorbed a s a f u n c t i o n o f time was e s t i m a t e d by t h e Loo-Riegelman method u s i n g t h e m a c r o s c o p i c r a t e c o n s t a n t s c a l c u l a t e d from t h e intravenous data. The s l o p e o f t h e l i n e a r p a r t o f t h e L o o Riegelman p l o t combined w i t h t h e t o t a l amount absorbed ( q u a n t i t a t e d by d e p l e t i o n a n a l y s i s o f t h e s a t u r a t e d donor s o l u t i o n ) was used t o c a l c u l a t e t h e z e r o - o r d e r r a t e c o n s t a n t f o r buccal permeability. RESULTS H i s t o l o g y o f t h e B u c c a l Mucosa. A l t h o u g h r o d e n t b u c c a l mucosa i s r e p o r t e d t o c o n s i s t o f b o t h k e r a t i n i z e d and n o n - k e r a t i n i z e d s t r i a t e d e p i t h e l i a , no e v i d e n c e f o r t h e l a t t e r was o b t a i n e d i n t h e p r e s e n t s t u d y . In a l l rodents examined, h e a v i l y k e r a t i n i z e d s t r i a t e d e p i t h e l i a were o b s e r v e d on t h e i n n e r c e n t r a l cheek ( s e e F i g u r e 1 f o r r a t ) . M u c o s a l s e c t i o n s exhibited c h a r a c t e r i s t i c e p i t h e l i a l c e l l d i f f e r e n t i a t i o n with c e l l s becoming p r o g r e s s i v e l y f l a t t e r and f o r m i n g a g r a n u l a r l a y e r w i t h i n c r e a s i n g d i s t a n c e from t h e b a s a l c e l l l a y e r . The o u t e r


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s u r f a c e was seen t o c o n s i s t e n t i r e l y o f a t h i c k a c e l l u l a r l a y e r . Dog ( F i g u r e 2) and p i g mucosa on t h e o t h e r hand e x h i b i t e d h i s t o l o g i c a l f e a t u r e s s i m i l a r t o t h o s e seen i n man. In both s p e c i e s t h e r e was no apparent k e r a t i n i z a t i o n i n t h e outward p r o g r e s s i o n o f e p i t h e l i a l c e l l s from t h e b a s a l l a y e r . Because o f i t s easy a v a i l a b i l i t y , t h e dog was s e l e c t e d as t h e most a p p r o p r i a t e a n i m a l model f o r subsequent i n v i v o a b s o r p t i o n studies.


In

V i t r o Drug R e l e a s e .

The c u m u l a t i v e r e l e a s e p r o f i l e f o r d i c l o f e n a c sodium from t h e t r a n s b u c c a l d e l i v e r y d e v i c e e x h i b i t e d a square r o o t o f time dependency o v e r a p p r o x i m a t e l y 80% of t h e t o t a l r e l e a s e p r o c e s s ( F i g u r e 3 ) . I n v i e w of t h e d r u g ' s s o l u b i l i t y w i t h i n t h e h y d r o g e l (-16 mg/cc) and t h e t o t a l l o a d i n g (-420 mg/cc), d r u g 2 e l e a s e was m o d e l l e d as a d i s p e r s e d m o n o l i t h and a 3.19 χ 10 cm /h d i f f u s i o n c o e f f i c i e n t was c a l c u l a t e d . r

In

Vivo Absorption Studies.

A l l a n i m a l s made a f u l l and u n e v e n t f u l r e c o v e r y from t h e e x p e r i m e n t a l p r o c e d u r e and no e v i d e n c e f o r drug o r p r o c e d u r a l r e l a t e d a d v e r s e r e a c t i o n s was o b t a i n e d . Mucosal t i s s u e b i o p s i e s showed no apparent damage a t t h e m i c r o s c o p i c l e v e l . The plasma coneentrâtion/time p r o f i l e f o r t h e 4 mg i n t r a v e n o u s dose e x h i b i t e d an i n i t i a l r a p i d f a l l o v e r 1-2 h f o l l o w e d by a slower d e c l i n e over 30 h. The e x p e r i m e n t a l d a t a were f i t t e d t o a b i e x p o n e n t i a l r a t e e q u a t i o n t o g i v e t h e f o l l o w i n g mean parameter v a l u e s : C(t)

(

3

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0

8

8

7

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where C ( t ) i s t h e plasma c o n c e n t r a t i o n i n ng/ml a t time t a f t e r dosing. The c l e a r a n c e v a l u e c a l c u l a t e d from t h i s d a t a was 12.99 ml/min and t h e t o t a l volume o f d i s t r i b u t i o n 8.9 1. Plasma c o n c e n t r a t i o n p r o f i l e s a f t e r b u c c a l a d m i n i s t r a t i o n o f the s a t u r a t e d drug s o l u t i o n v a r i e d c o n s i d e r a b l y between a n i m a l s but t h e o v e r a l l time dependency was s i m i l a r ( F i g u r e 4 ) . Plasma l e v e l s i n c r e a s e d r a p i d l y a f t e r a p p l i c a t i o n o f t h e s o l u t i o n onto the mucosa t o produce r e l a t i v e l y c o n s t a n t c o n c e n t r a t i o n s i n t h e range 1500-8000 ng/ml a f t e r 2 h. F o l l o w i n g removal o f t h e s o l u t i o n t h e drug e x h i b i t e d t h e e x p e c t e d d e c l i n e i n plasma c o n c e n t r a t i o n s a t a r a t e comparable t o t h a t o b s e r v e d i n t h e intravenous bolus study. Loo-Riegelman a n a l y s e s o f t h e i n d i v i d u a l a b s o r p t i o n s t u d i e s showed t h a t t h e f r a c t i o n o f t h e t o t a l absorbed v a r i e d l i n e a r l y w i t h t i m e o v e r most of t h e 4 h a p p l i c a t i o n p e r i o d ( F i g u r e 5 ) . T h e r e was l i t t l e e v i d e n c e f o r a s i g n i f i c a n t l a g phase and t h e



E B E R T ET AL.


F i g u r e 1. B u c c a l Mucosa o f t h e Rat - e p i d e r m i s c o v e r e d by t h i c k k e r a t i n i z e d l a y e r l i n i n g t h e cheek. T h i s t y p e o f cheek pouch l i n i n g was seen i n a l l r o d e n t s s t u d i e d , i n c l u d i n g mouse, g u i n e a p i g , r a t and r a b b i t .

F i g u r e 2. B u c c a l Mucosa o f t h e Dog - e p i d e r m i s w i t h t h e absence of a d e f i n e d s t r a t u m corneum, s i m i l a r t o t h e human i n n e r cheek.


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v a r i a t i o n between a n i m a l s a f t e r a d j u s t i n g f o r t h e t o t a l amount absorbed was s m a l l . The a v e r a g e z e r o - o r d e r r a t e c o n s t a n t 2 f o r b u c c a l a b s o r p t i o n c a l c u l a t e d from t h i s d a t a was 2.8 mg/cm .h. The pH o f a s a t u r a t e d d i c l o f e n a c s o l u t i o n was d e t e r m i n e d t o be 8.28, n e a r l y 5 u n i t s above i t s pKa ( 3 . 1 ) . A t t h i s pH t h e drug i s c o m p l e t e l y i o n i z e d s u g g e s t i n g t h a t t h e b u c c a l mucosa can be h i g h l y permeable t o charged s p e c i e s . Plasma c o n c e n t r a t i o n s o f d i c l o f e n a c sodium a f t e r a p p l i c a t i o n of t h e t r a n s b u c c a l d e l i v e r y d e v i c e ( F i g u r e 6) f o l l o w e d a d i f f e r e n t time c o u r s e t o t h a t o b s e r v e d w i t h t h e s a t u r a t e d solution. Plasma c o n c e n t r a t i o n s o f t h e drug i n c r e a s e d r a p i d l y over t h e i n i t i a l phase and a c h i e v e d peak v a l u e s o f 2400-4000 ng/ml a t 1 h a f t e r system a p p l i c a t i o n . T h e r e a f t e r , t h e l e v e l s d e c r e a s e d s l o w l y and converged t o a mean v a l u e o f 2250 ng/ml b e f o r e t h e system was removed. Based on d e p l e t i o n a n a l y s i s , 7.8 mg was d e l i v e r e d on a v e r a g e from t h e h y d r o g e l d i s c s over 4 h . Not u n e x p e c t e d l y t h e Loo-Riegelman p l o t s f o r t h e b u c c a l d e v i c e d i f f e r e d from t h o s e f o r t h e s a t u r a t e d s o l u t i o n and e x h i b i t e d n o n - l i n e a r v a r i a t i o n w i t h time ( F i g u r e 7 ) . Drug r e l e a s e from t h e d e v i c e was m o d e l l e d on t h e b a s i s o f a membrane d i s p e r s e d m o n o l i t h (3) f o r which t h e n e t f l u x i s g i v e n by

2t DC

(À-0.5C (2)

where J , J , C and A r e p r e s e n t n e t f l u x , maximum membrane f l u x , s a t u r a t i o n w i t h i n t h e m o n o l i t h and t o t a l l o a d i n g . Integrating the above f l u x e q u a t i o n g i v e s :

DC

(A-

0.5C )

HI

3 Q

Transbuccal Absorption of Diclofenac Sodium in a Dog Model - ACS

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