Solubilisierung stark lipophiler Arzneistoffe in lipidhaltige ...

Summary
layers of aggregates. These differences reflected themselves particularly in the obtained
cybotactic polarity results and they were accounted for the aforementioned exceptional
solubilization behavior of testosterone in HTAB systems.
Except for the last case (testosterone in HTAB systems), the results revealed a similar
solubilization behavior for steroids in all studied surfactant systems. That is an increasing
solubilization of the testosterone derivatives along with the increase in their side chain
length, and thus their lipophilicity, up to a defined number of carbon atoms in the
straight side chain (about 7-9 C atoms) after which any further increase in the side chain
length leads to a decline in the solubilization. Discussing this finding in the light of other
results in this work, especially the corresponding cybotactic polarity changes, it was
stated that, besides the structure and size of aggregates and the distribution of polar and
apolar sites in drug and aggregate structures, other structural factors could play here an
important role in the solubilization of studied model drugs. These factors are the size
and lipophilicity of drug molecules as well as the strength of adhesion between the
different hydrocarbon moieties within the aggregate interior. With increasing drug
lipophilicity, the drug affinity to the lipophilic solubilizing sites within the aggregates
grows too, leading accordingly to an improvement of drug solubilization in the aggregate
system. However, it becomes more difficult to incorporate highly lipophilic drugs with
very large molecules, since they may hereby disturb the whole aggregate structure. They
may penetrate deep into the aggregate core, causing the packing of hydrocarbon
moieties there to become very tight, and thus hinder the conformational adaptations
needed for optimal molecular interactions within the aggregate structure. Consequently,
the aggregates become less stable and the solubilization of drug molecules in the
system declines. In conclusion, a compromise between all above-mentioned factors
should be achieved, while developing such mixtures, in order to obtain optimal drug
solubilization. Among the compared testosterone esters, TE best fulfills the structural
requirements for the incorporation within the studied aggregate systems due to its
medium side chain length and it gives accordingly the best solubilization results.
However, for the same reason, the saturation of the different micellar surfactant systems
with TE gave despite the filtration (∅ 45 µm) milky, over days stable dispersions,
indicating thus the formation of highly aggregated structures such as vesicles at such
high drug concentrations.
One of the most important factors influencing the micellar delivery of highly lipophilic
drugs to lipid membranes was found to be the difference in drug affinities between both
phases, the membrane and the micellar phase. This factor finds particularly an
expression in the drug partition coefficient K (membrane/micelles). Accordingly, changes
leading to an increase in drug solubilization or rather in drug binding interactions with
the aggregate phase without a similar increase in drug affinity to the membrane (i.e. lipid
addition to the micellar system) brought about a decrease in drug delivery to the
membrane. Furthermore, increasing drug lipophilicity while K > 0.5 led in general to an
enhancement of the micellar drug delivery to the membranes (i.e. NaGDC systems) The
same increase in drug lipophilicity led to a decrease in drug absorption when K < 0.5
(i.e. Br35 and HTAB systems).
A known equation based on the second Fick’s law describing the unsteady diffusion into
an almost impermeable membrane for a given compound was used in this work to
derive a nonlinear function describing time dependant changes in drug concentrations
at the donator side of a diffusion model. Using the permeation model of Fürst-Neubert,
the function was applied to estimate the values of K and D M (Diffusion coefficient of drug
in the membrane) and to test their possible changes in relationship to the used micellar
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