EVALUATION OF INTESTINAL PRESSURE-CONTROLLED COLON DELIVERY CAPSULE CONTAINING CAFFEINE AS A MODEL-DRUG IN HUMAN VOLUNTEERS

The delivery ability of a pressure-controlled colon delivery capsule ( PCDC) containing caffeine as a test drug was evaluated after oral admi nistration to healthy male human volunteers. The driving force causing PCDC disintegration in the intestinal tract is the physiological lumi nal pressure which results from peristalsis. Three kinds of PCDCs havi ng different thickness of a water-insoluble polymer membrane were prep ared by coating the inner surface of the gelatin capsules with ethylce llulose (EC). The mean thicknesses were 40+/-1 (S,E.) for type 1, 44+/ -1 for type 2 and 50+/-1 mu m for type 3 PCDC, respectively. Caffeine was dissolved with a suppository base (PEGs 400 and 1000) and the caps ules were filled. Doses were 15, 45 or 75 mg. After blank saliva sampl es were obtained, test preparations were orally administered to the vo lunteers and saliva samples were collected for 1 min intervals hourly from 1 to 10 h in the fasted state study, and from 1 to 20 h and at 25 h in the fed state study. Caffeine concentrations in the saliva sampl es were analyzed by HPLC. The maximum salivary caffeine excretion rate increased as the oral caffeine dose increased. The maximum salivary c affeine excretion rate increased predominantly compared to the pre-dos e level in 75 mg dose study. Therefore, all following studies were per formed with this dose. The first appearance time of caffeine into the saliva, T-i was used as a parameter to estimate the disintegration tim e of test preparations in the gastrointestinal tract. The mean T-i of types 1, 2, and 3 PCDCs were 3.0+/-0.4, 4.0+/-0.4 and 4.5+/-0.3 h, res pectively. After oral administration of 75 mg caffeine in plain gelati n capsule as a reference preparation, caffeine appeared in the saliva within 0.5 h. The mean hardness of the PCDCs were 1.05+/-0.10 (type 1) , 1.55+/-0.06 (type 2) and 2.08+/-0.15 newton (type 3), respectively. There were good correlations between three parameters: EC coating memb rane thickness, hardness and T-i (determination coefficient r(2)=0.935 between T-i and thickness, r(2)=0.998 between thickness and hardness, r(2)=0.958 between hardness and T-i). The effect of food intake on th e delivery ability was examined with type 3 PCDCs. Food intake prolong ed the mean T-i from 4.5+/-0.3 to 7.8+/-1.3 h, This increase is though t to be ascribed to prolonged gastric emptying time. Comparison with r eported colon arrival times indicates that the type 3 PCDC functions i n colon delivery of caffeine and is thought to be applicable to other drugs. (C) 1998 Elsevier Science B.V.