Solubilisierung stark lipophiler Arzneistoffe in lipidhaltige ...

Summary
carriers. The derived function demonstrated an excellent fitting to the absorption data
obtained in this work by using the mentioned permeation model. The obtained K values
for TP and TE carried by Br35 mixed micellar systems were almost identical, whereas
detected D M for TE was, unexpectedly, significantly smaller as compared with it for TP.
This revealed that besides the increased drug affinity to the micellar phase, other
important factors are possibly involved in this case. The most likely ones are the high
polarity of the hydrated polyoxyethylen layer of Br35 micelles or an interfacial surfactant
boundary layer developed on the membrane surface which may exhibit upon an increase
in drug lipophilicity an increasing resistance to drug transfer from the aggregate interior
into the membrane.
Further experiments were conducted using the Ussing chamber and excised segments
from mice small intestine in order to study the influence of drug lipophilicity and used
micellar carriers on drug delivery in small intestine. The above mentioned rule of
differences in drug affinities proved to be valid here as well, both quantitatively, in term
of drug solubilization, and qualitatively, in term of strength of drug binding interactions
with a considered phase. Accordingly, a weak drug delivery was obtained by using the
micellar systems of HTAB as drug carriers for testosterone and TP, whereas no delivery
was detected with the more lipophilic esters such as TE. This was simply attributed to
the aforementioned high solubilizing capacity of those systems toward the studied highly
lipophilic drugs, which naturally increases with lipid addition or increasing drug
lipophilicity. However, other factors were believed to contribute to the reduced drug
delivery here such as the high polarity of the superficial micellar layer, as indicated by the
cybotactic polarity measurements, and the electrostatic repulsion between the positively
charged micelles and membrane surfaces.
In summary, an ideal micellar carrier system for the delivery of highly lipophilic drugs to
a mucosal membrane should demonstrate an almost identical affinity to the drug as
compared to the epithelial cell membrane, and a rather small hydratation grade or
polarity in its superficial layers as well as a possibly neutral or negative surface electric
charge. This may seem contradictory for the development of such systems, since one
expects in this case from an ideal micellar system to present also a high solubilizing
capacity for such drugs. Furthermore, the membrane damaging effect known to be
induced by surfactants and in particular their micellar systems gives rise to lipid addition
to these systems, based on the known protective or mitigating role of lipids in such
cases. However, this addition leads in most cases to an enhancement of the solubilization
of highly lipophilic drugs (increasing drug affinity to the micelles) and to a possible
increase in the hydratation grade of the superficial micellar layers, as seen in cases
studied in this work. Therefore, the formulation of the mixture should take those factors
also into account and try to find a compromise between them in order to achieve an
optimal drug delivery by means of these carrier systems. Nevertheless, the improvement
of the solubilization of highly lipophilic drugs by using such lipid-containing mixed
micellar systems as drug carriers remains beneficial and particularly attractive under
many aspects and as long as the drug inclusion within the micelles does not lead to a
strong hindrance of the drug delivery to the membranes. One of the most important
reasons is that these systems enable highly lipophilic drugs to overcome the mucus
layer, one of the most crucial barriers to their transport to the epithelial cell membrane in
the gastrointestinal tract. Furthermore, these Systems usually help to solubilize such
drugs in sufficient amounts and to improve drug dissolution rate, which could be in
many instances, and particularly here in the case of such drugs, the rate limiting step for
drug transport, thereby leading finally to a substantial improvement of drug absorption.
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