Solubilisierung stark lipophiler Arzneistoffe in lipidhaltige ...

Summary
In all selected surfactant systems, no substantial changes in aggregate sizes were
noticed after the addition of steroids in concentrations adequately below the saturation
values. A remarkable increase in aggregate sizes was first obtainable after lipid addition.
This was associated in the case of NaGDC with the formation of the well known large
bile salt-lecithin mixed micelles whose structure is still to date a subject of wide argument.
In the case of Br35, the aggregate growth was interpreted by the incorporation of
OS molecules into the region of surfactant hydrocarbon moieties to form together a
distinct fluid-like hydrophobic core in the aggregate interior, and thereby leading to an
enlargement of the whole aggregate. The increase of the micellar size following OS
addition to the HTAB system was attributed to the formation of rod-like mixed micelles.
The change in the micellar size was independent of the added model drugs to the lipidcontaining
binary systems of NaGDC or Br35, whereas it showed a dependency on the
molecular characteristics of added steroids (i.e. ester chain length and lipophilicity) in
the case of OS containing HTAB mixed systems. The last observation was considered to
confirm an active contribution of the added testosterone derivatives to the formation of
the rod-like micellar structure, brought about most likely by increasing the packing
parameter (PP) in the micellar assembly as a direct result of the amphiphilic character of
these drugs.
Although the growth in the micellar size in the case of the mixed micellar systems of
NaGDC is coupled with an increase in the aggregation number of the surfactant
molecules, the measurements with micellar affinity capillary electrophoresis indicated no
significant change in the effective mobility of the micelles. This was ascribed, in
compliance with other works, to a decrease in the net surface charge density of the
micelles, induced by the incorporation of lecithin molecules. Despite the high amount of
solubilized OS in Br35 systems, no significant change was detected in the surface
electric charge of aggregates. Accordingly, this confirmed the inclusion of almost all OS
molecules into the aggregate core, in a way that they were not able to effectively
influence the surface electric charge. In contrast, the low amounts of solubilized OS
molecules in HTAB systems induced a considerable increase of surface positive electric
charge of micelles due to the formation of large rod-like structures with a high
aggregation number of surfactant molecules.
Furthermore, measurements of the cybotactic polarity in the vicinity of the conjugated
cyclic ketone functions of the solubilized steroids indicated an increase in the polarity of
the surrounding environment after lipid addition to NaGDC and Br35 systems (except for
solubilizing TU in Br35 systems), whereas this addition in the case of HTAB systems led
to a decrease in the cybotactic polarity around the mentioned ketone functions. The first
observation was attributed to an increased hydratation grade at the superficial layers of
aggregates, whereas the second observation pertained most likely to a shift of steroids
embedding sites to deeper positions in the micellar structure due to a reduced adhesion
between the hydrocarbon chains in the micellar interior following the lipid addition.
The obtained results suggested also that testosterone differs entirely from its esters in
their arrangement ways within the aggregates. Whereas its polarity and relatively small
molecular size cause testosterone to be embedded in the more hydrophilic solubilizing
sites adjacent to the layer of polar surfactant head groups in the aggregates, its esters
incorporate themselves deeper in more hydrophobic sites within the aggregate interior
due to their increased lipophilicity and molecular sizes. It was additionally concluded,
that the testosterone molecule arranges itself within the aggregates in an entirely
opposite way as compared with its esters by directing its ketone group toward the
aggregate interior while its hydroxyl group remains anchored within the superficial polar
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