Dj. Pillion et al., STRUCTURE-FUNCTION RELATIONSHIP AMONG QUILLAJA SAPONINS SERVING AS EXCIPIENTS FOR NASAL AND OCULAR DELIVERY OF INSULIN, Journal of pharmaceutical sciences, 85(5), 1996, pp. 518-524
The purpose of this investigation was to explore the structure-functio
n relationship among naturally occurring Quillaja saponins and derivat
ives for their ability to stimulate insulin delivery from nosedrops an
d eyedrops and to test the hypothesis that stimulation of peptide drug
delivery was correlated with surfactant strength. Native saponins, in
cluding QS-21, were purified from an aqueous extract of Quillaja sapon
aria bark by adsorption chromatography and HPLC. Native saponins were
then deacylated by mild alkaline hydrolysis to form DS-1 and DS-2, der
ivatives that are smaller and more hydrophilic than their parent compo
unds. DS-1 was further treated either to reduce an aldehyde residue to
form DS-1(R) or to remove the fucose-containing oligosaccharide to fo
rm QH-957. Rats receiving eyedrops or nosedrops formulated with insuli
n, but without any Quillaja saponins, showed no hypoglycemic response.
Rats receiving eyedrops or nosedrops formulated with insulin plus sap
onins showed a dose-dependent hypoglycemic response, with the followin
g rank order: QS-21 > DS-1 > DS-1(R) > DS-2 > QH-957. Surfactant stren
gth was determined by measurement of the critical micellar concentrati
on (cmc) and hemolysis of sheep erythrocytes. The cme was lowest for t
he parent saponins QS-21 and QS-18, and increased for the deacylated s
aponin derivatives DS-1, DS-2, and QH-957; hemolysis of sheep erythroc
ytes was observed at low concentrations (similar to 0.006 mM) of the p
arent saponins, QS-21 and QS-18, at intermediate concentrations (0.06-
0.08 mM) of DS-1 and DS-2, and at higher concentrations of DS-1(R) (0.
45 mM) and QH-957 (1.5 mM). Hence, efficacy as an absorption-enhancing
agent was greatest in those saponins with the lowest hemolytic titers
and cmc values. However, this relationship was not a strict one, beca
use DS-1, which differs from DS-2 only in the absence of one glucose r
esidue, was significantly more potent than DS-2 in stimulating the abs
orption of insulin. DS-1 and DS-2 share a similar cmc and hemolytic ti
ter, so this difference in efficacy must be due to some specificity be
yond simple surfactant strength. Furthermore, DS-1 does not trigger an
immune response when administered to animals, whereas QS-21 is a stro
ng immune system activator. Therefore, DS-1 has emerged as an interest
ing candidate for inclusion in an eyedrop or nosedrop formulation.