In vivo performance of an oral MR matrix tablet formulation in the beagle dog in the fed and fasted state: assessment of mechanical weakness.
OBJECTIVE
To evaluate the behaviour of an oral matrix modified release formulation in the canine gastrointestinal tract, and establish if a mechanical weakness previously observed in clinical studies would have been identified in the dog model.


METHODS
In vitro release profiles were obtained for two modified release matrix tablets containing UK-294,315, designed to release over either 6 (formulation A) or 18 (formulation B) hours. Tablets were labelled with (153)samarium and in vivo pharmacoscintigraphy studies were performed in four beagle dogs in the fasted state for both formulations, and following ingestion of an FDA high fat meal for formulation B.


RESULTS
The matrix tablet formulations displayed significantly different in vitro release profiles (F (2) < 50), with time to 80% release for formulation A and B of 406 and 987 min respectively. Complete in vivo disintegration occurred at 339 +/- 181 and 229 +/- 171 for formulation A and B respectively in the fasted state, and at 207 +/- 154 min for formulation B in the fed state, in disagreement with in vitro release.


CONCLUSIONS
The fed/fasted dog model would have predicted a lack of physical robustness in the matrix tablet formulation B, however it would not have predicted the clear fed/fasted effects on performance observed previously in man.
McInnes
Fiona
F
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. fiona.mcinnes@strath.ac.uk
Clear
Nicola
N
Humphrey
Michael
M
Stevens
Howard N E
HN
D000818:Animals; D019540:Area Under Curve; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004285:Dogs; D004339:Drug Compounding; D005215:Fasting / Q000378:metabolism*; D005772:Gastrointestinal Transit; D006245:Hardness Tests; D007275:Injections, Intravenous; D019999:Pharmaceutical Solutions; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry; D011868:Radioisotopes / Q000493:pharmacokinetics; D012493:Samarium / Q000493:pharmacokinetics; D012995:Solubility; D013607:Tablets
C483030:4-amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-(4-(morpholinocarbonyl)--perhydro-1,4-diazepin-1-yl)quinoline; D001381:Azepines; D003692:Delayed-Action Preparations; D019999:Pharmaceutical Solutions; D011804:Quinolines; D011868:Radioisotopes; D013607:Tablets; D012493:Samarium