ABSTRACT
The aims of this study were two-fold; first to report on the use of the novel InteliSite Companion device to deliver material to the colon, and second to use this new technology to assess the potential of mucoadhesive polymers to be retained in the large intestine. In this three-way crossover study in beagle dogs, two mucoadhesive polymers and a non-mucoadhesive polymer were remotely delivered in powder form to the colon. The retention of 150mg doses of the radiolabelled mucoadhesive polymers Carbopol 980 and polycarbophil AA-1, and the retention of ethylcellulose (control) in the colon of three canines was examined using gamma scintigraphy. The InteliSite Companion device had a mean gastric emptying time of 1.0+/-0.8h and a mean caecal arrival time of 2.3+/-1.0h. The device was remotely activated to expel the polymers at the caecum. Although incomplete release was noted with all polymers, Carbopol 980 was found to have increased retention in the proximal colon of all three dogs. The mean retention time within the proximal colon for Carbopol 980 (15.3+/-1.4h) was significantly higher than that of polycarbophil AA-1 (10.0+/-5.7h) and the control (7.1+/-1.4h) (p<0.05). The increased colon retention time demonstrated by Carbopol 980 may be suggestive of a mucoadhesive effect.
Subject(s)
Mucous Membrane , Polymers/administration & dosage , Tissue Adhesives , Animals , Cross-Over Studies , Dogs , MaleABSTRACT
PURPOSE: To develop a robust radiolabeling technique to enable evaluation of difficult to radiolabel gastric retentive formulations using gamma scintigraphy. The use of a successful radiolabel will allow accurate assessment of the gastric residence time of the formulations. MATERIALS AND METHODS: The retention of two radionuclides, indium ((111)In) and samarium ((153)Sm), with and without further processing to improve radiolabel performance were evaluated in simulated gastric pH in vitro. The most successful formulation from the in vitro screening was further evaluated in preclinical and clinical studies. RESULTS: In vitro evaluation revealed significant radionuclide leakage at pH 1.5 for most radiolabeling attempts. Radionuclide leakage at pH 4.5 was less pronounced. The most successful radiolabel was formulated by adsorbing indium chloride onto activated charcoal, followed by entrapment in a cellulose acetate polymer melt. This provided the best radiolabel retention under both pH conditions in vitro. The radiolabel also proved to be successful during preclinical and clinical evaluations, allowing evaluation of gastric retention performance as well as complete gastrointestinal transit. CONCLUSION: A simple, yet robust radiolabel was developed for gastric retentive formulations to be evaluated pre-clinically or in a clinical setting by entrapping the radionuclide in an insoluble polymer through a simple polymer melt process.
Subject(s)
Gastric Emptying , Indium/administration & dosage , Isotope Labeling/methods , Oxides/administration & dosage , Radiopharmaceuticals/administration & dosage , Samarium/administration & dosage , Stomach/diagnostic imaging , Technology, Pharmaceutical/methods , Administration, Oral , Adult , Animals , Cellulose/analogs & derivatives , Cellulose/chemistry , Charcoal/chemistry , Chemistry, Pharmaceutical , Cross-Over Studies , Delayed-Action Preparations , Dogs , Drug Compounding , Drug Stability , Gamma Cameras , Gastrointestinal Transit , Half-Life , Humans , Hydrogen-Ion Concentration , Indium/chemistry , Male , Middle Aged , Oxides/chemistry , Radioisotopes/administration & dosage , Radionuclide Imaging , Radiopharmaceuticals/chemistry , Samarium/chemistry , Solubility , Time FactorsABSTRACT
Previous work has shown that polyethylene glycol 400 (PEG 400) has an accelerating effect on gastrointestinal transit and a modulating influence on drug absorption in humans. The aim of this study was to assess the impact of various excipients, PEG 400, propylene glycol, d-alpha-tocopheryl-polyethylene glycol-1000 succinate (TPGS) and Labrasol on gastrointestinal transit and drug absorption in four beagle dogs using scintigraphy. Each dog received, on five separate occasions, water (control) or a dose of excipient equivalent to 1 g PEG 400, 2 g propylene glycol, 1 g TPGS or 2 g Labrasol dissolved in water and administered in the form of two capsules. The model drugs ampicillin (200mg) and antipyrine (100mg) were co-administered in the capsules. The capsule solutions were radiolabelled with technetium-99m to follow their transit using a dual-headed gamma camera, and blood samples were collected to determine drug pharmacokinetics. On a separate occasion, the drugs were dissolved in saline and given intravenously. The capsules rapidly disintegrated in the stomach liberating their liquid contents. The mean small intestinal transit times for the different treatments (control, PEG 400, propylene glycol, TPGS and Labarasol) were 183, 179, 195, 168 and 154 min, respectively. The corresponding mean absolute oral bioavailability figures were 36, 32, 39, 42 and 32% for ampicillin and 76, 74, 85, 73 and 74% for antipyrine, respectively. The transit and bioavailability data for the excipient treatments were not significantly different from the control. In summary, these excipients, at the doses administered, have limited influence on gastrointestinal transit and drug in beagle dogs.
