Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 648

resulted in more recent work concentrating on the optimization of enhancement
strategies. A widespread array of enhancers has been used to overcome the difficul-
ties associated with poor and erratic availability following rectal administration, with
some limited success. Nonionic surfactants and glycerol esters have been used to
deliver therapeutic amounts of insulin and nonionic surfactants in a polyacrylic acid
gel. Bile salts have been used to deliver interferon-1 and insulin. However, given
the damaging effects of bile salts on the mucosa and the possible carcinogenic effects
of rectally administered bile salts, safer enhancers have been developed.
Yoshikawa et al. [166] have demonstrated the successful enhancement of recom-
binant -interferon using suppositories containing lipid-surfactant mixed micelles
composed of linoleic acid (0.5%) and HCO-60 (0.4%), a polyoxyethylene castor oil
derivative. -Interferon entered the lymph circulation in superior proportion to the blood
compartment. The same researchers investigated the enhancing effects of another mixed
micelle formulation, monoolein/sodium taurocholate with dextran sulfate, on bleomy-
cin absorption. Once again they demonstrated a preferential uptake into lymph and a
significant degree of absorption enhancement. In anesthetized rats, Miyake et al. [162]
showed that [Asu 1,7]-eel calcitonin (5 U kg) dosed rectally achieved a bioavailability
of 0.6% relative to intramuscular administration. However, the presence of an enhancer,
polyacrylic acid gel, increased absorption from the rectum, producing a significant
hypocalcemic response. For some forms of treatment, the rectal route could provide a
more acceptable alternative to multiple injections. It is evident from the studies cited
that peptide and protein delivery is strongly influenced by numerous formulation factors
and does require the careful use of enhancing agents. However, this mode of delivery
shares many problems with the oral and nasal route. It is difficult to predict widespread
use of peptide and protein formulations suitable for rectal delivery [163,167-170] .
12.4.3 Advantages and Disadvantages of Peptide and Protein Drug
Delivery Through the Rectal Route
The transition from columnar to stratified epithelium in the rectum permits rapid
absorption of low-molecular-weight proteins and peptide. The rectal site provides
potential for absorption into the lymphatic system, which may be due to large pore
radii in the rectum. The rectum allows retaining a large volume of formulation at the
site of application (10-25 ml). The potential for time-controlled release and repro-
ducible absorption is higher at the rectum due to constant environment at the site of
application.
Specifically, the advantages for rectal delivery of peptides and proteins are sum-
marized here: the rectal route has low levels of pancreatic-originated protease activ-
ity. The rectal route provides a large surface area for absorption that is potentiated
by using spreading/foaming agents in the formulation. The rectal route avoids the
first-pass metabolism of proteins and peptides because middle and inferior rectal
veins drain into the inferior vena cava. The disadvantages for rectal delivery of
drugs include poor or erratic absorption across the rectal mucosa of many drugs and
a limiting absorbable surface area. Slow dissolution of the formulation is due to the
small fluid content in the rectum.