Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: A crossover study with melatonin

被引:61
作者
Benes, L
Claustrat, B
Horriere, F
Geoffriau, M
Konsil, J
Parrott, KA
DeGrande, G
McQuinn, RL
Ayres, JW
机构
[1] 3M CO, PHARMACEUT, ST PAUL, MN 55144 USA
[2] LABS 3M SANTE, F-45312 PITHIVIERS, FRANCE
[3] CTR MED NUCL, F-69394 LYON 03, FRANCE
[4] OREGON STATE UNIV, COLL PHARM, CORVALLIS, OR 97331 USA
关键词
D O I
10.1021/js970011z
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called ''square-wave'' profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.
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页码:1115 / 1119
页数:5
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