Effect of colonic lactulose availability on the timing of drug release onset in vivo from a unique colon-specific drug delivery system (CODES).
OBJECTIVE
To test the hypothesis that the onset of drug release in vivo from a unique colon-specific drug delivery system (CODES) would depend on the colonic availability rate of lactulose. The site specificity of drug release in canine GI tract was also estimated.


METHODS
CODES tablets were prepared by tableting the granulation or acetaminophen and lactulose, followed with film coating. The pharmacokinetic performance of different CODES formulations was evaluated in six beagle dogs under fasted conditions. The release of acetaminophen and lactulose was also characterized in vitro.


RESULTS
The onset of acetaminophen release in beagle dogs was found to be dependent on the coating level of Eudragit E and lactulose loading in the core tablet. At Eudragit E coating levels of 4%, 8% and 12% (coating weight gain), the onset of in vivo drug release occurred 5.5 (+/- 1.9) h. 4.8 (+/-1.0) h. and 7.5 (+/-1.0) h, respectively, after dosing. A similar trend was observed when the loading of lactulose in the core tablet decreased from 78% to 58% and 38%. However, the rate and extent of acetaminophen absorption did not vary significantly in each situation based on the values of AUC and Cmax.


CONCLUSIONS
The onset of drug release in vivo from CODES tablets is predominantly dependent on colonic availability rate of lactulose because drug release from this system is triggered by localized drop of colonic pH from the fermentation of lactulose.
Yang
Libo
L
Yamanouchi Pharma Technologies, Inc., Palo Alto, California 94304, USA. lyang@ICOS.com
Watanabe
Shunsuke
S
Li
Jinhe
J
Chu
James S
JS
Katsuma
Musataka
M
Yokohama
Shigeharu
S
Fix
Joseph A
JA
D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D003106:Colon / Q000378:metabolism*; D004285:Dogs; D016503:Drug Delivery Systems; D007792:Lactulose / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011109:Polymethacrylic Acids / Q000737:chemistry; D012995:Solubility; D013608:Tablets, Enteric-Coated; D013997:Time Factors
D011109:Polymethacrylic Acids; D013608:Tablets, Enteric-Coated; C038300:methylmethacrylate-methacrylic acid copolymer; D000082:Acetaminophen; D007792:Lactulose