Promoted rectal absorption of insulin: formulative parameters involved in the absorption from hydrophilic bases

Abstract

The profiles of the hypoglycaemic activity of rectally-administered insulin in hydrophilic bases containing various types of polyethoxylated non-ionic surfactants as promoters was measured as a function of important parameters involved in the formulation. Relatively high surfactant concentrations were used to minimize surfactant concentration membrane dependence. Screening revealed surfactant chain-length dependencies and also high activities in sorbitan esters similar to those found in some straight chain ethers; e.g. Myrj 45, a straight chain ester, was low in activity. In the polysorbate series, a regular dependence of activity on surfactant lipophilic chain-length was found with EO 20 and EO 4, efficiency falling off on raising C from 12 to 18. Oleate was more active than stearate. In the PEG base dependence on carbon chain-length was not found for the EO 20 series but there was strong activity over the range. HLB change may be involved but is not the main factor. Insulin absorption from promoting bases was strongly affected by pH, being minimal at pH 5.2. Without promoters, however, activity was low and pH-dependence absent. A non-linear dose-dependence profile was found in the range 12–150 I.U./kg with maxima and minima in both bases, the polyacrylate base being somewhat more active than the PEG base. The insulin activity was persistently high but the positions of the maxima and minima indicated clearly that the activity and formation of insulin aggregates is a significant factor. The important parameter affecting insulin activity in rectal formulations are promoter chemical structure, pH, carrier and insulin dose-level, all of which influence the chemical as well as the biological activity.