Colonic delivery of dexamethasone: a pharmacoscintigraphic evaluation.
BACKGROUND
Colonic delivery of corticosteroids may reduce the side-effects commonly associated with their use. Therefore, we tested the ability of the naturally occurring polysaccharide guar gum to deliver a corticosteroid, dexamethasone, to the colon using pharmacoscintigraphy. Guar gum is metabolized in the colon by resident bacterial enzymes to trigger drug release.


METHODS
Each subject (eight per group, parallel study design) was administered one of four dexamethasone (9 mg) tablet formulations, radiolabelled with 153Sm using neutron activation, under fasted conditions. One formulation was designed to release drug rapidly following ingestion while the other three formulations were designed to delay release of dexamethasone to varying degrees. Progression of the formulations down the gastrointestinal tract was followed by gamma scintigraphy. Serum concentrations were measured over time to relate disintegration profiles of the tablets with pharmacokinetic observations.


RESULTS
The immediate release formulation disintegrated in the stomach, on average, within 20 min of dosing. One of the three delayed release preparations (CD1) began to disintegrate in the small intestine 1.7 +/- 1.0 h after dosing. The second and third delayed release preparations (CD2 and CD3) did not begin to disintegrate until 5.8 +/- 2.3 and 3.6 +/- 1.6 h after dosing, respectively. All three colonic delivery preparations completely disintegrated in the colon ranging from 7.8 +/- 2.7 h (CD1) to 12.4 +/- 3.2 h (CD2) following oral administration. Pharmacoscintigraphic data indicated that 72-82% of the dexamethasone was delivered into the colon although not all the dexamethasone delivered into the colon was absorbed.


CONCLUSIONS
Simple guar gum formulations are capable of delivering the corticosteroid dexamethasone to the colon of normal subjects. Locally delivered corticosteroids may be useful in the treatment of ulcerative colitis and Crohn's disease. Pharmacoscintigraphic evaluation is a useful method to discriminate between the in vivo behaviour of colonic delivery systems.
Kenyon
C J
CJ
Pharmaceutical Profiles Ltd, Highfields Science Park, Nottingham, UK.
Nardi
R V
RV
Wong
D
D
Hooper
G
G
Wilding
I R
IR
Friend
D R
DR
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003106:Colon / Q000000981:diagnostic imaging / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D005685:Galactans / Q000008:administration & dosage*; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008351:Mannans / Q000008:administration & dosage*; D008657:Metabolic Clearance Rate; D053149:Plant Gums; D011868:Radioisotopes; D011877:Radionuclide Imaging; D012493:Samarium
D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D005685:Galactans; D005938:Glucocorticoids; D008351:Mannans; D053149:Plant Gums; D011868:Radioisotopes; D012493:Samarium; D003907:Dexamethasone; C007894:guar gum