IN-VIVO STUDIES OF AMYLOSE-COATED AND ETHYLCELLULOSE-COATED [C-13] GLUCOSE MICROSPHERES AS A MODEL FOR DRUG-DELIVERY TO THE COLON

The observation that certain starches naturally present in the diet re sist pancreatic enzymes and reach the colon where they are fermented b y bacterial amylases has been exploited to provide a coating for speci fically targeting drugs to the human large intestine. A mixture of amy lose, which is a fraction of starch that can be made resistant to panc reatic enzymes, and Ethocel (1:4 amylose:Ethocel) has been developed a nd [C-13]glucose used as a surrogate for drug delivery. Eight healthy subjects were given, fasting, at 8 am amylose-Ethocel coated pellets c ontaining 300 mg [C-13]glucose together with a further capsule that co ntained amberlite resin labelled with Tc-99m to act as a transit marke r and outline for the anatomy of the gut. Subjects underwent gamma-sci ntigraphy at half-hourly intervals for 5 h and then at hourly interval s until 8 pm. Breath samples were taken for (CO2)-C-13, which was meas ured by gas isotope mass spectrometry, at half-hourly intervals for 5 h and then hourly until 2300 h, with two further breath samples the fo llowing morning before breakfast. Gamma-scintigraphy showed that 5% of the activity had arrived in the caecum at 3.5 h after oral dosage (ra nge 2.5-4.75 h) with all the material in the colon after 7.1 h (4.5-10 h). Breath (CO2)-C-13 data were analysed by the cusum technique and b y curve fitting to determine first appearance of (CO2)-C-13 in breath. The first rise in breath (13)CO2 was at 3.5 h (range 2.0-6.0 h) with 1% accumulated recovery of breath (CO2)-C-13 at 6.2 h (5.2-7.3 h). Tot al (CO2)-C-13 recovery at 25 h was 37.5% (21.9-47.8%). A single subjec t given a dose of uncoated glucose showed a rise in breath (CO2)-C-13 at 30 min peaking at 1.5 h and a total recovery of 28% at 6 h. Accumul ated recovery curves for (CO2)-C-13 in breath showed that pellet break down and glucose metabolism was occurring over a 15 h period with a de lay of about 2.7 h between arrival in the caecum and significant (1%) breakdown of the pellets. Resistant amylose, a naturally occurring com ponent of the diet combined with ethylcellulose, can therefore be used to coat pellets that allow controlled release of contents for targete d drug delivery to the large bowel during a 12-24 h period.