|dc.description.abstract||Since its initial discovery in 1922 by Banting and Best, the formulation of an oral insulin delivery system has ever been so troublesome. Unfortunately, insulin is indispensable in the treatment of diabetes mellitus, which affects approximately 350 million people worldwide. Various factors contribute to the peptide being such a persistently difficult hormone to be used in an oral formulation. The gastrointestinal tract is home to various protein digestive enzymes such as pepsins in the stomach and trypsin, chymotrypsin and carboxypeptidases in the small intestine, which digests insulin. Also the physical barrier of the gastrointestinal tract, i.e. the columnar epithelial layer which lines the tract, is a tightly bound collection of cells with minimal leakage and is thus a sound barrier for the
absorption of peptides and hormones. The aim of this study is to determine whether a dosage form for insulin, entrapped in Pheroid™ vesicles and -micro sponges, can overcome these barriers and successfully deliver insulin at the site of action resulting in a significant therapeutic response.
Initial phases of the study consisted of the manufacturing of Pheroid™ vesicles and -
microsponges, entrapment of flourescein-isothiocyanate labelled insulin (FITC-insulin)
into the Pheroid™. The Pheroid™-insulin complex was analysed with confocal laser
scanning microscopy (CLSC) to determine drug loading. In vivo experiment in Sprague -
Dawley rats were done where blood glucose levels as well as insulin blood levels were
monitored after administration of different Pheroid insulin formulations. Firstly a
standard reference was set by subcutaneous injection of insulin (0.5 IU/kg) in rats
followed by a comparative study where administration to the stomach, colon and ileum
(50.0 IUlkg insulin) were compared by means of blood insulin levels and therapeutic
effect between the control and Pheroid™ complexes (Pheroid™ vesicles and microsponges).
Each study was done by means of direct injection into the stomach, ileum or
colon through which the insulin in saline (control) or insulin-Pheroid™ complex was
administered. Nasal administration of 8.0 and 12.0 IU/kg insulin in saline (control) or
insulin-Pheroid™ complex was done in the right nostril of Sprague - Dawley rats. Blood
samples were taken from the artery carotis communis by means of an inserted cannula.
Blood samples were taken just before administration and then at 5, 10, 15, 30, 60, 120
and 180 minutes after administration. Blood glucose levels were measured just after
every blood sample was taken and plasma insulin levels were determined with a human
insulin specific radioimmunoassay. The results were compared to the reference as well
as the control to determine relative bioavailability.
Through the results obtained it was discovered that in comparison with the various parts
of the or tract, the ileum showed undoubtedly to be the best area of absorption where
Pheroid™ vesicles revealed a peak 42.0 % lowering in blood glucose levels after 60
minutes and a peak plasma concentration of 244.0 /uID/ml after 5 minutes together with
an 18.7 % lowering in blood glucose levels after just 5 minutes. After nasal
administration of Pheroid™ microsponges (8.0 ID/kg insulin) a remarkable lowered
blood glucose level of 19.2 % after 10 minutes and 36.5 % after 30 minutes as well as a
peak plasma insulin level of220.2 /lID/ml after 3 hours was observed. Insulin entrapped
in Pheroid™ microsponges administered at 12.0 ID/kg showed a maximum blood
glucose lowering effect of72.4 % after 3 hours with a peak plasma level of 154.8 uID/ml
also after 3 hours, thus showing a long acting effect.
In conclusion, the delivery system based on Pheroid™ technology shows a sufficient
therapeutic effect for insulin and is therefore promising for further in vivo evaluation and
ultimately for medicinal use to patients suffering from diabetes mellitus.||