Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.
Pulsincap formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro-in vivo correlation for time of release from Pulsincap preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.
Stevens
Howard N E
HN
Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, G4 0NR, Glasgow, UK. h.n.e.stevens@strath.ac.uk
Wilson
Clive G
CG
Welling
Peter G
PG
Bakhshaee
Massoud
M
Binns
Julie S
JS
Perkins
Alan C
AC
Frier
Malcolm
M
Blackshaw
Elaine P
EP
Frame
Margaret W
MW
Nichols
Don J
DJ
Humphrey
Michael J
MJ
Wicks
Steve R
SR
D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D004341:Drug Evaluation / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000889:Anti-Arrhythmia Agents; D002214:Capsules; D003692:Delayed-Action Preparations; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide