Rectal administration route limitations

Medicinal products administered at a specific site to obtain a local effect should preferably not be absorbed systemically. However, significant amounts of active substance can be absorbed, e.g. after application on the skin. Removal of locally acting active substances from the site of action by systemic absorption may result in systemic effects that can be considered as adverse effects. After nasal, ocular, pulmonary and rectal administration of active substances for a local effect, absorption into the systemic circulation is likely to occur. This may cause adverse effects and limit the duration of the desired drug effect. Conversely it should be realised that the systemic route is often also the main route for clearance of the active substance from the site of administration. The bioavaUability of locally acting medicines is, of course, not determined by the amount of active substance that reaches the systemic circulation. As an alternative the fraction of the active substance that is dissolved in the aqueous fluids at the site of application is usually taken as a measure for the bioavailability. 

One of the key pieces to development of a successful drug product is the ability to deliver the drug to the site of action with minimal discomfort or inconvenience to the patient. For small molecule therapeutics, there is a wide range of options available for drug administration. Delivery via injection (IV, IM, and SC), oral, nasal, ocular, transmucosal (buccal, vaginal, and rectal), and transdermal routes is possible with small molecule drugs. However, the size of proteins and the complexity of their structures severely limit the routes of administration available to proteins. 

The rectal cavity has the potential of convenient access and easy administration of suppositories or gels, although patient acceptance of rectal delivery is low in some cultures. It has a limited surface area (de Boer et al, 1992) and relatively high proteolytic activity (Lee et al, 1987), but with respect to administration of insulin the rectal route offers the particular physiological advantage of potential delivery, via the upper rectal veins, into the portal system. This would mimic the natural secretion of insulin and result in reduced peripheral hyperinsulinemia. However, nearly two-thirds of the insulin absorbed firom the rectum reaches the general circulation via the lymphatic pathway (Caldwell et al, 1982). 

The ocular, buccal, rectal, and vaginal routes of administration all have inherent limitations and serious drawbacks for delivery of insulin and therefore are highly unlikely to be of any use for chronic insulin therapy. 

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