A canine biorelevant dissolution method for predicting in vivo performance of orally administered sustained release matrix tablets.
Preclinical species are a crucial component of drug development, but critical differences in physiology and anatomy need to be taken into account when attempting to extrapolate to humans or between species. The same is true when trying to develop oral formulations for preclinical species, especially unconventional formulations, such as sustained release tablets. During the evaluation of such specialized dosage forms, dissolution can be a critical in vitro tool used to rank-order formulations and ultimately choose the desired release rate. Here, the development of a canine biorelevant dissolution method for the prediction of the in vivo performance of sustained release matrix tablets in beagle dogs is described. The method accounts for differences in physiology between humans and dogs such as gastrointestinal fluid composition, gastric emptying forces, and gastric residence time. The most critical dissolution method parameters were found to be the paddle speed used to simulate the gastric emptying forces as well as the time spent in simulated gastric fluid. The resulting differences in method conditions are further explored through in silico models of the hydrodynamic forces applied to a dosage form. Two case studies are reported showing that the method was able to obtain excellent in vitro-in vivo relationships (slopes ranging from 1.08-1.01) which are significantly (p < 0.01-0.05) improved compared to human biorelevant dissolution used to predict in vivo performance in humans (slopes ∼1.5-1.75). The quality of the method's predictive ability allows for it to help drive the development of matrix sustained release formulations intended for preclinical studies.
a Department of Analytical Sciences, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Rahway , NJ , USA .
Paul L
PL
Walsh
a Department of Analytical Sciences, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Rahway , NJ , USA .
Jameson R
JR
Bothe
b Department of Discovery Pharmaceutical Sciences, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Kenilworth , NJ , USA .
Sunny
S
Bhardwaj
b Department of Discovery Pharmaceutical Sciences, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Kenilworth , NJ , USA .
Mengwei
M
Hu
c Department of Biopharmaceutics, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , West Point , PA , USA , and.
Rebecca
R
Nofsinger
c Department of Biopharmaceutics, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , West Point , PA , USA , and.
Binfeng
B
Xia
d Department of Device Development, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Rahway , NJ , USA.
Steven
S
Persak
a Department of Analytical Sciences, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Rahway , NJ , USA .
Justin
J
Pennington
b Department of Discovery Pharmaceutical Sciences, Pharmaceutical Sciences & Clinical Supplies , Merck Research Laboratories , Kenilworth , NJ , USA .
Annette
A
Bak
D000284:Administration, Oral; D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000378:metabolism*; D004285:Dogs; D005746:Gastric Emptying / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism; D005766:Gastrointestinal Contents; D006801:Humans; D008954:Models, Biological; D012995:Solubility; D013607:Tablets / Q000737:chemistry* / Q000378:metabolism*
D003692:Delayed-Action Preparations; D013607:Tablets
Controlled release; in vitro prediction; in vitro–in vivo correlation; preclinical species; predictive technologies