INFLUENCE OF AMOUNT OF HARD FAT IN SUPPOSITORIES ON THE IN-VITRO RELEASE RATE AND BIOAVAILABILITY OF PARACETAMOL AND CODEINE .1. A COMPARISON OF 3 SUPPOSITORY COMPOSITIONS IN-VIVO

The flow-through cell at a flow rate of 16 and 8 ml/min has been used to investigate how the amount of paracetamol and codeine phosphate, in relation to the total weight of a lipophilic suppository, influences the in vitro dissolution rate. Two in vivo studies explored how the rate and extent of bioavailability in humans varied as a function of fraction of drug substances. Despite an approx. 20-fold difference in aqueous solubility between paracetamol and codeine phosphate, the lipophilicity controlled the in vitro release and bioavailability. Decreasing the amount of paracetamol and codeine phosphate in relation to total suppository weight and increasing the size of the suppository resulted in a faster absorption rate and an increased extent of bioavailability. This was more pronounced for paracetamol. The flow-through cell was found to produce dissolution profiles which were in agreement with the plasma concentration profiles obtained, indicating that the lower Bow rate reflected the in vivo situation more correctly than the higher flow rate. The intra-individual variation when administering one composition on two different occasions was found to be relatively small for five of the subjects who participated in both studies.